Tricyclic and tetracyclic taxane intermediates

ABSTRACT

The synthesis of taxol and other tricyclic and tetracyclic taxanes.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional and continuation-in-part ofcopending application Ser. No. 08/189,058, filed Jan. 27, 1994, which isa continuation-in-part of copending, application Ser. No. 08/138,229,filed Oct. 15, 1993, which is a continuation-in-part of copendingapplication Ser. No. 08/095,161, filed Jul. 20, 1993. This applicationis also a continuation-in-part of PCT/US94/08350, filed Jul. 20, 1994.

[0002] This invention was made with Government support under NIH Grant#CA 42031 awarded by the National Institutes of Health. The UnitedStates Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0003] The present invention is directed to the synthesis of taxol andother tricyclic and tetracyclic taxanes and novel intermediates thereof.

[0004] The taxane family of terpenes, of which taxol is a member, hasattracted considerable interest in both the biological and chemicalarts. Taxol is a promising cancer chemotherapeutic agent with a broadspectrum of antileukemic and tumor-inhibiting activity. Taxol has thefollowing structure:

[0005] wherein Ac is acetyl.

[0006] The supply of taxol is presently being provided by the bark fromTaxus brevifollia (Western Yew). However, taxol is found only in minutequantities in the bark of these slow growing evergreens. Consequently,chemists in recent years have expended their energies in trying to finda viable synthetic route for the preparation of taxol. To date, theresults have not been entirely satisfactory.

[0007] A semi-synthetic approach to the preparation of taxol has beendescribed by Greene, et al. in JACS 110, 5917 (1988), and involves theuse of a congener of taxol, 10-deacetyl baccatin III which has thestructure of formula II shown below:

[0008]10-deacetyl baccatin III is more readily available than taxolsince it can be obtained from the needles of Taxus baccata. According tothe method of Greene et al., 10-deacetyl baccatin III (“10-DAB”) isconverted to taxol by attachment of the C-10 acetyl group and byattachment of the C-13 β-amido ester side chain through theesterification of the C-13 alcohol with a β-amido carboxylic acid unit.

[0009] Denis et al. in U.S. Pat. No. 4,924,011 disclose another processfor preparing derivatives of baccatin III or of 10-deacetylbaccatin IIIof general formula

[0010] in which R′ denotes hydrogen or acetyl. As reported, an acid ofgeneral formula:

[0011] in which R₁ is a hydroxy-protecting group, is condensed with ataxane derivative of general formula:

[0012] in which R₂ is an acetyl hydroxy-protecting group and R₃ is ahydroxy-protecting group, and the protecting groups R₁, R₃ and, whereappropriate, R₂ are then replaced by hydrogen.

[0013] Other semisynthetic approaches for the preparation of taxol andfor the preparation of other taxanes which possess tumor-inhibitingproperties have been reported in recent years, but each of theseapproaches requires 10-DAB or baccatin III as a starting material. Assuch, the supply of taxol and other taxane derivatives remains dependentat least to some extent upon the collection of various parts of plantsfrom the remote corners of the world and the extraction of 10-DAB and/orbaccatin III therefrom.

SUMMARY OF THE INVENTION

[0014] Among the objects of the present invention, therefore, is theprovision of a process for the synthesis of taxol and other tetracyclictaxanes; the provision of such a process which is highlydiastereoselective; the provision of such a process which proceeds inrelatively high yield; and the provision of key intermediates andprocesses for their preparation.

[0015] Briefly, therefore, the present invention is directed to aprocess for the preparation of taxol and other tricyclic and tetracyclictaxanes.

[0016] In accordance with one aspect of the present invention, theprocess comprises reacting a compound having the formula

[0017] with BrMgN(iPr)₂, an aldehyde (or ketone), followed by phosgeneand an alcohol to form a compound having the formula:

[0018] wherein

[0019] R₁ is hydrogen or protected hydroxy; R₂ is hydrogen or protectedhydroxy;

[0020] R₃ is oxo;

[0021] R_(7b) is hydrogen, alkyl, cyano, hydroxy, protected hydroxy, or—OCOR₃₆;

[0022] R_(7c) and R_(7d) are independently hydrogen, alkyl, alkenyl,alkynyl, aryl or heteroaryl;

[0023] R₉ is hydrogen, protected hydroxy, or oxo;

[0024] R₁₀ is —OP₁₀;

[0025] R₁₃ is —OP₁₃;

[0026] R₃₆ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy,—NX₈X₁₀, —SX₁₀, monocyclic aryl or monocyclic heteroaryl;

[0027] X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0028] X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

[0029] P₁₀ and P₁₃ are hydroxy protecting groups.

[0030] In accordance with another aspect of the present 10 invention,the process comprises reacting a compound having the formula

[0031] with lithium tetramethylpiperidide to form a compound having theformula:

[0032] wherein

[0033] R₁ is hydrogen or protected hydroxy;

[0034] R_(7c) is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

[0035] R₉ is hydrogen, protected hydroxy, or oxo; and

[0036] P₁₀ and P₁₃ are hydroxy protecting groups.

[0037] In accordance with another aspect of the present invention, theprocess comprises reacting a compound having the formula:

[0038] with lithium tetramethylpiperidide and camphosulfonyl oxaziridineto form a compound having the formula:

[0039] wherein R₉ is hydrogen, protected hydroxy, or oxo; R_(7c) ishydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; and P₁₀ and P₁₃are hydroxy protecting groups.

[0040] In accordance with another aspect of the present invention, theprocess comprises reacting a compound having the formula:

[0041] with a hydride reducing agent, preferably Red-Al, to form acompound having the formula:

[0042] wherein R₉ is hydrogen, protected hydroxy, or oxo; R_(7c) ishydrogen, alkyd, alkenyl, alkynyl, aryl or heteroaryl; and P₁₀ and P₁₃are hydroxy protecting groups.

[0043] In accordance with another aspect of the present invention, theprocess comprises reacting a compound having the formula:

[0044] with lithium diisopropylamide to form a compound having theformula:

[0045] wherein R is lower alkyl, R₁ is hydrogen, protected hydroxy or R₁and R₂ together form a carbonate, R₂ is hydrogen, protected hydroxy orR₁ and R₂ together form a carbonate, R₉ is hydrogen, protected hydroxy,or oxo; and P₁₀ and P₁₃ are hydroxy protecting groups.

[0046] In accordance with another aspect of the present invention, theprocess comprises reacting a compound having the formula:

[0047] with DBU to form a compound having the formula:

[0048] wherein

[0049] R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, ortogether with R₂ is a carbonate;

[0050] R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, ortogether with R₁ is a carbonate;

[0051] R_(4a) is hydrogen, alkyl, hydroxy, or protected hydroxy, ortogether with R₂ is a carbonate;

[0052] R_(4b) is hydroxymnethylene;

[0053] R₅ is —OMs, —OTs or a bromide;

[0054] R_(7a) is hydrogen, protected hydroxy, or —OCOR₃₄, or togetherwith R₉ is a carbonate;

[0055] R₉ is hydrogen, oxo, hydroxy, protected hydroxy, or —OCOR₃₃, ortogether with R_(7a) or R₁₀ is a carbonate;

[0056] R₁₀ is hydrogen, oxo, hydroxy, protected hydroxy, or —OCOR₂₉ ortogether with R₉ is a carbonate;

[0057] P₁₃ is a hydroxy protecting group;

[0058] R_(29,) R₃₀, R₃₁ R₃₃ and R₃₄ are independently hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclic aryl ormonocyclic heteroaryl;

[0059] X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

[0060] X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl.

[0061] In accordance with another aspect of the present invention, theprocess comprises reacting a compound having the formula:

[0062] with KOtBu and (PhSeO)₂O to form a compound having the formula:

[0063] which rearranges in the presence of additional KOtBu, silica gel,or other acids or bases, or with heat to a compound having the formula:

[0064] wherein

[0065] R₁ is hydrogen, hydroxy, protected hydroxy, or —OCOR₃₀, ortogether with R₂ is a carbonate;

[0066] R₂ is hydrogen, protected hydroxy, or —OCOR₃₁, or together withR₁ or R_(4a) is a carbonate;

[0067] R_(4a) is hydrogen, alkyl, hydroxy, protected hydroxy, or—OCOR₂₇, together with R_(4b) is an oxo, or together with R₂, R_(4b), orR₅ is a carbonate;

[0068] R_(4b) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, orcyano, together with R_(4a) is an oxo, together with R_(4a) or R₅ is acarbonate, or together with R₅ and the carbons to which they areattached form an oxetane ring;

[0069] R₅ is hydrogen, protected hydroxy, —OCOR₃₇ together with R_(4a)or R_(4b) is a carbonate, or together with R_(4b) and the carbons towhich they are attached form an oxetane ring;

[0070] R_(7a) is hydrogen, halogen, protected hydroxy, or —OCOR₃₄;

[0071] P₁₃ is a hydroxy protecting group;

[0072] R₂₇, R₃₀, R₃₁, R₃₄ and R₃₇ are independently hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclic aryl ormonocyclic heteroaryl;

[0073] X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl; and

[0074] X₁₀ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl.

[0075] In general, the process of the present invention may be used toprepare taxanes having the formula:

[0076] wherein

[0077] R₁ is hydrogen, hydroxy, protected hydroxy, or —OCOR₃₀;

[0078] R₂ is hydrogen, hydroxy, —OCOR₃₁, or oxo;

[0079] R_(4a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,cyano, hydroxy, —OCOR₂₇, or together with R_(4b) forms an oxo, oxiraneor methylene;

[0080] R_(4b) is hydrogen, together with R_(4a) forms an oxo, oxirane ormethylene, or together with R₅ and the carbon atoms to which they areattached form an oxetane ring;

[0081] R₅ is hydrogen, halogen, hydroxy, protected hydroxy, —OCOR₃₇,oxo, or together with R_(4b) and the carbon atoms to which they areattached form an oxetane ring;

[0082] R₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl,hydroxy, protected hydroxy or together with R_(6a) forms an oxo;

[0083] R_(6a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl,hydroxy, protected hydroxy or together with R₆ forms an oxo;

[0084] R_(7a) is hydrogen, halogen, hydroxy, protected hydroxy, —OCOR₃₄,oxo, or —OR₂₈;

[0085] R₉ is hydrogen, hydroxy, protected hydroxy, acyloxy, or oxo;

[0086] R₁₀ is hydrogen, —OCOR₂₉, hydroxy, protected hydroxy, or oxo;

[0087] R₁₃ is hydroxy, protected hydroxy, MO— or

[0088] R₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0089] R_(14a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl, hydroxy, protected hydroxy or together with R₁ forms acarbonate;

[0090] R₂₈ is a functional group which increases the solubility of thetaxane;

[0091] R₂₇, R₂₉, R₃₀, R₃₁, R₃₄ and R₃₇ are independently hydrogen,alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl;

[0092] X₁ is —OX₆, —SX₇, or —NX₈X₉;

[0093] X₂ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0094] X₃ and X₄ are independently hydrogen, alkyl, alkenyl, alkynyl,aryl, or heteroaryl;

[0095] X₅ is —COX₁₀, —COOX₁₀, —COSX₁₀, —CONX₈X₁₀, or —SO₂X₁₁;

[0096] X₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,hydroxy protecting group, or a functional group which increases thewater solubility of the taxane derivative;

[0097] X₇ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydrylprotecting group;

[0098] X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;

[0099] X₉ is an amino protecting group;

[0100] X₁₀ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl;

[0101] X₁₁ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OX₁₀, or—NX₈X₁₄;

[0102] X₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;and

[0103] M comprises ammonium or is a metal.

[0104] The present invention is additionally directed to an intermediatefor use in the preparation of a tricyclic or tetracyclic taxane havingthe formula:

[0105] wherein

[0106] R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, ortogether with R₂ is a carbonate;

[0107] R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, ortogether with R₁ is a carbonate;

[0108] R₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₂, or oxo;

[0109]₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

[0110] R₉ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₃, ortogether with R₁₀, is a carbonate;

[0111] R₁₀ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₂₉, ortogether with R₉ is a carbonate;

[0112] R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅ or MO—;

[0113] R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₅ are independently hydrogen,alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclicaryl or monocyclic heteroaryl;

[0114] X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0115] X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

[0116] M comprises ammonium or is a metal.

[0117] The present invention is further directed to an intermediate foruse in the preparation of a tricyclic or tetracyclic taxane having theformula:

[0118] wherein

[0119] R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, ortogether with R₂ is a carbonate;

[0120] R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, ortogether with R₁ is a carbonate;

[0121] R₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₂, or oxo, ortogether with R_(7b) is a carbonate;

[0122] R_(7b) is hydrogen, alkyl, cyano, hydroxy, protected hydroxy, or—OCOR₃₆, or together with R₃ or R₉ is a carbonate;

[0123] R_(7c) and R_(7d) are independently hydrogen, alkyl, alkenyl,alkynyl, aryl or heteroaryl;

[0124] R₉ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₃, ortogether with R_(7b) or R₁₀ is a carbonate;

[0125] R₁₀ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₂₉, ortogether with R₉ is a carbonate;

[0126] R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅ or MO—;

[0127] R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₅ and R₃₆ are independently hydrogen,alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclicaryl or monocyclic heteroaryl;

[0128] X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0129] X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

[0130] M comprises ammonium or is a metal.

[0131] The invention is further directed to an intermediate for use inthe preparation of a tricyclic or tetracyclic taxane having the formula:

[0132] wherein

[0133] R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, ortogether with R₂ is a carbonate;

[0134] R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, ortogether with R₁ is a carbonate;

[0135] R₃ is hydrogen, hydroxy, protected hydroxy, or —OCOR₃₂;

[0136] R_(7b) is hydrogen, alkyl, cyano, hydroxy, protected hydroxy, or—OCOR₃₆;

[0137] R_(7c) is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

[0138] R₉ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₃, ortogether with R₁₀ is a carbonate;

[0139] R₁₀ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₂₉, ortogether with R₉ is a carbonate;

[0140] R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅ or MO—;

[0141] R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₅ and R₃₆ are independently hydrogen,alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclicaryl or monocyclic heteroaryl;

[0142] X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0143] X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

[0144] M comprises ammonium or is a metal.

[0145] The present invention is further directed to an intermediate foruse in the preparation of a tricyclic or tetracyclic taxane having theformula:

[0146] wherein

[0147] R is C₁-C₈ alkyl,

[0148] R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, ortogether with R₂ is a carbonate;

[0149] R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁,together with R₁ is a carbonate, or together with R₄ is a carbonate;

[0150] R_(4a) is hydrogen, alkyl, hydroxy, protected hydroxy, or—OCOR₂₇, or together with R₂ is a carbonate;

[0151] R_(7a) is hydrogen, halogen, hydroxy, protected hydroxy, —OR₂₈,—OCOR₃₄, or together with R₉ is a carbonate;

[0152] R₉ is hydrogen, oxo, hydroxy, protected hydroxy, —OR₂₈, or—OCOR₃₃ or together with R_(7a) or R₁₀ is a carbonate;

[0153] R₁₀ is hydrogen, oxo, hydroxy, protected hydroxy, —OR₂₈, or—OCOR₂₉, or together with R₉ is a carbonate;

[0154] R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅ or MO—;

[0155] R₂₈ is a functional group which increases the solubility of thetaxane derivative;

[0156] R₂₇, R₂₉, R₃₀, R₃₁, R₃₃, R₃₄, and R₃₅ are independently hydrogen,alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclicaryl or monocyclic heteroaryl;

[0157] X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0158] X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

[0159] M comprises ammonium or is a metal.

[0160] The invention is further directed to an intermediate for use inthe preparation of a tricyclic or tetracyclic taxane having the formula:

[0161] wherein

[0162] R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, ortogether with R₂ is a carbonate;

[0163] R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, ortogether with R₁ or R_(4a) is a carbonate;

[0164] R_(4a) is hydrogen, alkyl, hydroxy, protected hydroxy, or—OCOR₂₇, together with R_(4b) is an oxo, or together with R₂, R_(4b), orR₅ is a carbonate;

[0165] R_(4b) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, orcyano, together with R_(4a) is an oxo, together with R_(4a) or R₅ is acarbonate, or together with R₅ and the carbons to which they areattached form an oxetane ring;

[0166] R₅ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₇, oxo,together with R_(4a) or R_(4b) is a carbonate, or together with R_(4b)and the carbons to which they are attached form an oxetane ring;

[0167] R_(7a) is hydrogen, halogen, hydroxy, protected hydroxy, —OR₂₈,or —OCOR₃₄, or together with R₉ is a carbonate;

[0168] R₉ is hydrogen, oxo,.hydroxy, protected hydroxy, —OR₂₈, or—OCOR₃₃, or together with R_(7a) or R₁₀ is a carbonate;

[0169] R₁₀ is hydrogen, oxo, hydroxy, protected hydroxy, —OR₂₈, or—OCOR₂₉, or together with R₉ is a carbonate;

[0170] R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅, MO— or

[0171] R₂₈ is a functional group which increases the solubility of thetaxane derivative;

[0172] R₂₇, R₂₉, R₃₀, R₃₁, R₃₃, R₃₄, R₃₅ and R₃₇ are independentlyhydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀,monocyclic aryl or monocyclic heteroaryl;

[0173] X₁ is —OX₆, —SX₇, or —NX₈X₉;

[0174] X₂ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0175] X₃ and X₄ are independently hydrogen, alkyl, alkenyl, alkynyl,aryl, or heteroaryl;

[0176] X₅ is —COX₁₀, —COOX₁₀, —COSX₁₀, —CONX₈X₁₀, or —SO₂X₁₁;

[0177] X₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,hydroxy protecting group, or a functional group which increases thewater solubility of the taxane derivative;

[0178] X₇ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydrylprotecting group;

[0179] X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0180] X₉ is an amino protecting group;

[0181] X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

[0182] X₁₁ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OX₁₀, or—NX₈X₁₄;

[0183] X₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;and

[0184] M comprises ammonium or is a metal.

[0185] The present invention is additionally directed to compoundshaving the formulae

[0186] wherein

[0187] R is lower alkyl,

[0188] T₄ is hydroxy or protected hydroxy,

[0189] T_(4a) and T_(4b) are independently alkoxy, alkoxycarbonyloxy,acyloxy, sulfonyloxy, hydroxy, or protected hydroxy, or together form acarbonate,

[0190] T₅ is alkoxy, alkoxycarbonyloxy, acyloxy, sulfonyloxy, hydroxy,or protected hydroxy,

[0191] P_(5,) P₇, P₁₀ and P₁₃ are hydroxy protecting groups, and

[0192] R₂, R_(4a), R_(7a), R_(10a), and R₁₃ are as previously defined.These compounds are key intermediates in the synthesis of taxol andother taxanes. The present invention is also directed to processes forthe preparation of these key intermediates.

[0193] Other objects and features of this invention will be in partapparent and in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0194] As used herein “Ar” means aryl; “Ph” means phenyl; “Me” meansmethyl; “Et” means ethyl; “iPr” means isopropyl; “tBu” and “t-Bu” meanstert-butyl; “R” means lower alkyl unless otherwise defined; “Ac” meansacetyl; “py” means pyridine; “TES” means triethylsilyl; “TMS” meanstrimethyl-silyl; “TBS” means Me₂t-BuSi—; “Tf” means “SO₂CF₃; “BMDA”meansBrMgNiPr₂; “Swern” means (COCl)₂, Et₃N; “LTMP” means lithiumtetramethylpiperidide; “MOP” means 2-methoxy-2-propyl; “BOM” meansbenzyloxymethyl; “LDA” means lithium diisopropylamide; “LAH” meanslithium aluminum hydride; “Red-Al” means sodium bis(2-methoxyethoxy)aluminum hydride; “Ms” means CH₃SO₂—; “TASF” meanstris(diethylamino)sulfonium-difluorotrimethylsilicate; “Ts” meanstoluenesulfonyl; “TBAF” means tetrabutyl ammonium hydride; “TPAP” meanstetrapropyl-ammonium perruthenate; “DBU” means diazabicycloundecane;“DMAP” means p-dimethylamino pyridine; “LHMDS” means lithiumhexamethyldisilazide; “DMF” means dimethylformamide; “AIBN” meansazo-(bis)-isobutyronitrile; “10-DAB” means 10-desacetylbaccatin III;“FAR” means 2-chloro-1,1,2-trifluorotriethylamine; “mCPBA” meansmetachloroperbenzoic acid; “DDQ” means dicyanodichloroquinone;“sulfhydryl protecting group” includes, but is not limited to,hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, orthiocarbonates; “amine protecting group” includes, but is not limitedto, carbamates, for example, 2,2,2-trichloroethylcarbamate ortertbutylcarbamate; “protected hydroxy” means —OP wherein P is a hydroxyprotecting group; and “hydroxy protecting group” includes, but is notlimited to, acetals having two to ten carbons, ketals having two to tencarbons, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl,p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl,ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilylethers such as trimethylsilyl ether, triethylsilyl ether,dimethylarylsilyl ether, triisopropylsilyl ether andt-butyldimethylsilyl ether; esters such as benzoyl, acetyl,phenylacetyl, formyl, mono-, di-, and trihaloacetyl such aschloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro-acetyl; andcarbonates including but not limited to alkyl carbonates having from oneto six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to sixcarbon atoms and substituted with one or more halogen atoms such as2,2,2-trichloroethoxymethyl and 2,2,2-tri-chloroethyl; alkenylcarbonates having from two to six carbon atoms such as vinyl and allyl;cycloalkyl carbonates having from three to six carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl orbenzyl carbonates optionally substituted on the ring with one or moreC₁₋₆ alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protectinggroups may be found in “Protective Groups in Organic Synthesis” by T. W.Greene, John Wiley and Sons, 1981.

[0195] The alkyl groups described herein are preferably lower alkylcontaining from one to six carbon atoms in the principal chain and up to15 carbon atoms. They may be straight or branched chain and includemethyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. They may behydrocarbon or heterosubstituted with the various substituents definedherein, including heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, aryl, heteroaryl, and heterosubstituted heteroaryl.

[0196] The alkenyl groups described herein are preferably lower alkenylcontaining from two to six carbon atoms in the principal chain and up to15 carbon atoms. They may be straight or branched chain and includeethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and thelike. They may be hydrocarbon or heterosubstituted with the varioussubstituents defined herein, including alkyl, heteroalkyl,heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, andheterosubstituted heteroaryl.

[0197] The alkynyl groups described herein are preferably lower alkynylcontaining from two to six carbon atoms in the principal chain and up to15 carbon atoms. They may be straight or branched chain and includeethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. They maybe hydrocarbon or heterosubstituted with the various substituentsdefined herein, including alkyl, heteroalkyl, alkenyl, heteroalkenyl,heteroalkynyl, aryl, heteroaryl, and heterosubstituted heteroaryl.

[0198] The aryl moieties described herein contain from 6 to 15 carbonatoms and include phenyl. They may be hydro-carbon or heterosubstitutedwith the various substituents defined herein, including alkyl,heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, heteroaryl,and heterosubstituted heteroaryl. Phenyl is the more preferred aryl.

[0199] The heteroaryl moieties described herein contain from 5 to 15atoms and include, furyl, thienyl, pyridyl and the like. They may behydrocarbon or heterosubstituted with the various substituents definedherein, including alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, aryl, and heterosubstituted heteroaryl.

[0200] The acyl moieties described herein contain alkyl, alkenyl,alkynyl, aryl or heteroaryl groups.

[0201] The alkoxycarbonyloxy moieties described herein comprise loweralkyl, alkenyl, alkynyl or aryl groups.

[0202] The hydrocarbon substituents described herein may be alkyl,alkenyl, alkynyl, or aryl, and the hetero-substituents of theheterosubstituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl moietiesdescribed herein contain nitrogen, oxygen, sulfur, halogens and/or oneto six carbons, and include lower alkoxy such as methoxy, ethoxy,butoxy, halogen such as chloro or fluoro, and nitro, heteroaryl such asfuryl or thienyl, alkanoxy, hydroxy, protected hydroxy, acyl, acyloxy,nitro, amino, and amido.

[0203] An exemplary synthesis of baccatin III or 10-DAB is depictedhereinbelow in Reaction Scheme A. The starting material, diol 2, can beprepared from patchino (commonly known as B-patchouline epoxide) whichis commercially available. The patchino is first reacted with anorgano-metallic, such as lithium t-butyl followed by oxidation with anorganic peroxide, such as t-butylperoxide in the presence of titaniumtetraisopropoxide to form a tertiary alcohol. The tertiary alcohol isthen reacted with a Lewis acid, such as boron trifluoride at lowtemperature, in the range from 40° C. to -100° C.; in the presence of anacid, such as trifluoromethane sulfonic acid. A graphical depiction ofthis reaction scheme along with an experimental write-up for thepreparation of diol 2 can be found in U.S. Pat. No. 4,876,399.

[0204] In Reaction Scheme A, P₅ is TMS, P₇ is MOP or BOM, P₁₀ is TES,P₁₃ is TBS, and R is ethyl in compounds 6 and 7, methyl in compounds 15,16, and 17, Ms in compounds 24aa and 26a, and Ts in compound 26aa. Itshould be understood, however, that P₅, P₇, P₁₀, and P₁₃ may be otherhydroxy protecting groups and R may comprise other lower alkylsubstituents in compounds 6, 7, 15, 16 and 17.

[0205] Reaction Scheme A may be varied between compounds 18 and 29 asset forth below in Reaction Scheme A′, with the reactions leading tocompound 18 and following compound 29 being as set forth in ReactionScheme A.

[0206] In Reaction Scheme A′, P₅ is TMS or Ac, P₇ is MOP or BOM, P₁₀ isTES, P₁₃ is TBS and P₅₂₀ is acetal or ketal, preferably acetonide. Itshould be understood, however, that P₅, P₇, P₁₀, and P₁₃ and P₅₂₀ may beother hydroxy protecting groups.

[0207] In general, tricyclic and tetracyclic taxanes bearing C13 sidechains may be obtained by reacting a β-lactam with alkoxides having thetaxane tricyclic or tetracyclic nucleus and a C-13 metallic oxidesubstituent to form compounds having a β-amido ester substituent atC-13. The β-lactams have the following structural formula:

[0208] wherein X₁-X₅ are as defined above. The alkoxides having thetricyclic or tetracyclic taxane nucleus and a C-13 metallic oxide orammonium oxide substituent have the following structural formula:

[0209] wherein R₁, R₂, R_(4a), R_(4b), R₅, R₆, R_(6a), R_(7a), R₉, R₁₀,R₁₄, and R_(14a) are as previously defined, R₁₃ is —OM and M comprisesammonium or is a metal optionally selected from Group IA, IIA,transition (including lanthanides and actinides), IIB, IIIA IVA, VA, orVIA metals (CAS version) . If M comprises ammonium, it is preferablytetraalkylarnmonium and the alkyl component of the tetraalkylammoniumsubstituent is preferably C₁-C₁₀ alkyl such as methyl or butyl. Mostpreferably, the alkoxide has the tetracyclic taxane nucleus andcorresponds to the structural formula:

[0210] wherein M, R₂, R_(4a), R_(7a), R₉, and R₁₀ are as previouslydefined.

[0211] As set forth in Reaction Scheme A, taxol may be prepared byconverting 7-protected Baccatin III 35 to the corresponding alkoxide andreacting the alkoxide with a β-lactam in which X₁ is protected hydroxy,X₃ is phenyl and X₅ is benzoyl. Protecting groups such as2-methoxypropyl (“MOP”), 1-ethoxyethyl (“EE”) are preferred, but avariety of other standard protecting groups such as the triethylsilylgroup or other trialkyl (or aryl) silyl groups may be used. Taxaneshaving alternative side chain substituents may be prepared through theuse of β-lactams which comprise the alternative substituents.

[0212] Taxanes having alternative C9 substituents may be prepared byselectively reducing the C9 keto substituent of taxol, 10-DAB, BaccatinIII or one of the other intermediates disclosed herein to yield thecorresponding C9 β-hydroxy derivative. The reducing agent is preferablya borohydride and, most preferably, tetrabutylammoniumboro-hydride(Bu₄NBH₄) or triacetoxyborohydride.

[0213] As illustrated in Reaction Scheme 1, the reaction of baccatin IIIwith Bu₄NBH₄ in methylene chloride yields 9-desoxo-9β-hydroxybaccatinIII 5. After the C7 hydroxy group is protected with the triethylsilylprotecting group, for example, a suitable side chain may be attached to7-protected-9β-hydroxy derivative 6 as elsewhere described herein.Removal of the remaining protecting groups thus yields 9β-hydroxy-desoxotaxol or other 9β-hydroxytetracylic taxane having a C13 side chain.

[0214] Alternatively, the C13 hydroxy group of 7-protected-9β-hydroxyderivative 6 may be protected with trimethylsilyl or other protectinggroup which can be selectively removed relative to the C7 hydroxyprotecting group as illustrated in Reaction Scheme 2, to enable furtherselective manipulation of the various substituents of the taxane. Forexample, reaction of 7,13-protected-9β-hydroxy derivative 7 with KHcauses the acetate group to migrate from C10 to C9 and the hydroxy groupto migrate from C9 to C10, thereby yielding 10-desacetyl derivative 8.Protection of the C10 hydroxy group of 10-desacetyl derivative 8 withtriethylsilyl yields derivative 9. Selective removal of the C13 hydroxyprotecting group from derivative 9 yields derivative 10 to which asuitable side chain may be attached as described above.

[0215] As shown in Reaction Scheme 3, 10-oxo derivative 11 can beprovided by oxidation of 10-desacetyl derivative 8. Thereafter, the C13hydroxy protecting group can be selectively removed followed byattachment of a side chain as described above to yield9-acetoxy-10-oxo-taxol or other 9-acetoxy-10-oxotetracylic taxaneshaving a C13 side chain. Alternatively, the C9 acetate group can beselectively removed by reduction of 10-oxo derivative 11 with a reducingagent such as samarium diiodide to yield 9-desoxo-10-oxo derivative 12from which the C13 hydroxy protecting group can be selectively removedfollowed by attachment of a side chain as described above to yield9-desoxo-10-oxo-taxol or other 9-desoxo-10-oxotetracylic taxanes havinga C13 side chain.

[0216] Reaction Scheme 4 illustrates a reaction in which 10-DAB isreduced to yield pentaol 13. The C7 and C10 hydroxyl groups of pentaol13 can then be selectively protected with the triethylsilyl or anotherprotecting group to produce triol 14 to which a C13 side chain can beattached as described above or, alternatively, after furthermodification of the tetracylic substituents.

[0217] Taxanes having C9 and/or C10 acyloxy substituents other thanacetate can be prepared using 10-DAB as a starting material asillustrated in Reaction Scheme 5. Reaction of 10-DAB withtriethylsilyl_.chloride in pyridine yields 7-protected 10-DAB 15. TheCIO hydroxy substituent of 7-protected 10-DAB 15 may then be readilyacylated with any standard acylating agent to yield derivative 16 havinga new C10 acyloxy substituent. Selective reduction of the C9 ketosubstituent of derivative 16 yields 9β-hydroxy derivative 17 to which aC13 side chain may be attached. Alternatively, the C10 and C9 groups canbe caused to migrate as set forth in Reaction Scheme 2, above.

[0218] Taxanes having alternative C2 and/or C4 esters can be preparedusing baccatin III and 10-DAB as starting materials. The C2 and/or C4esters of baccatin III and 10-DAB can be selectively reduced to thecorresponding alcohol(s) using reducing agents such as LAH or Red-Al,and new esters can thereafter be substituted using standard acylatingagents such as anhydrides and acid chlorides in combination with anamine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine.Alternatively, the C2 and/or C4 alcohols may be converted to new C2and/or C4 esters through formation of the corresponding alkoxide bytreatment of the alcohol with a suitable base such as LDA followed by anacylating agent such as an acid chloride.

[0219] Baccatin III and 10-DAB analogs having different substituents atC2 and/or C4 can be prepared as set forth in Reaction Schemes 6-10. Tosimplify the description, 10-DAB is used as the starting material. Itshould be understood, however, that baccatin III derivatives or analogsmay be produced using the same series of reactions (except for theprotection of the C10 hydroxy group) by simply replacing 10-DAB withbaccatin III as the starting material. 9-desoxo derivatives of thebaccatin III and 10-DAB analogs having different substituents at C2and/or C4 can then be prepared by reducing the C9 keto substituent ofthese analogs and carrying out the other reactions described above.

[0220] In Reaction Scheme 6, protected 10-DAB 3 is converted to thetriol 18 with lithium aluminum hydride. Triol 18 is then converted tothe corresponding C4 ester using Cl₂CO in pyridine followed by anucleophilic agent (e.g., Grignard reagents or alkyllithium reagents).

[0221] Deprotonation of trial 18 with LDA followed by introduction of anacid chloride selectively gives the C4 ester. For example, when acetylchloride was used, trial 18 was converted to 1,2 diol 4 as set forth inReaction Scheme 7.

[0222] Trial 18 can also readily be converted to the 1,2 carbonate 19.Acetylation of carbonate 19 under vigorous standard conditions providescarbonate 21 as described in Reaction Scheme 8; addition ofalkyllithiums or Grignard reagents to carbonate 19 provides the C2 esterhaving a free hydroxyl group at C4 as set forth in Reaction Scheme 6.

[0223] As set forth in Reaction Scheme 9, other C4 substituents can beprovided by reacting carbonate 19 with an acid chloride and a tertiaryamine to yield carbonate 22 which is then reacted with alkyllithiums orGrignard reagents to provide 10-DAB derivatives having new substituentsat C2.

[0224] Alternatively, baccatin III may be used as a starting materialand reacted as shown in Reaction Scheme 10. After being protected at C7and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol24. Tetraol 24 is converted to carbonate 25 using Cl₂CO and pyridine,and carbonate 25 is acylated at C10 with an acid chloride and pyridineto produce carbonate 26 (as shown) or with acetic anhydride and pyridine(not shown). Acetylation of carbonate 26 under vigorous standardconditions provides carbonate 27 which is then reacted with alkyllithiums to provide the baccatin III derivatives having new substituentsat C2 and C10.

[0225]10-desacetoxy derivatives of baccatin III and 10-desoxyderivatives of 10-DAB may be prepared by reacting baccatin III or 10-DAB(or their derivatives) with samarium diiodide. Reaction between thetetracyclic taxane having a C10 leaving group and samarium diiodide maybe carried out at 0° C. in a solvent such as tetrahydrofuran.Advantageously, the samarium diiodide selectively abstracts the C10leaving group; C13 side chains and other substituents on the tetracyclicnucleus remain undisturbed. Thereafter, the C9 keto substituent may bereduced to provide the corresponding 9-desoxo-9β-hydroxy-10-desacetyoxyor 10-desoxy derivatives as otherwise described herein.

[0226] C7 dihydro and other C7 substituted taxanes can be prepared asset forth in Reaction Schemes 11, 12 and 12a.

[0227] As shown in Reaction Scheme 12, Baccatin III may be convertedinto 7-fluoro baccatin III by treatment with FAR at room temperature inTHF solution. Other baccatin derivatives with a free C7 hydroxyl groupbehave similarly. Alternatively, 7-chloro baccatin III can be preparedby treatment of baccatin III with methane sulfonyl chloride andtriethylamine in methylene chloride solution containing an excess oftriethylamine hydrochloride.

[0228] Taxanes having C7 acyloxy substituents can be prepared as setforth in Reaction Scheme 12a, 7,13-protected 10-oxo-derivative 11 isconverted to its corresponding C13 alkoxide by selectively removing theC13 protecting group and replacing it with a metal such as lithium. Thealkoxide is then reacted with a β-lactam or other side chain precursor.Subsequent hydrolysis of the C7 protecting groups causes a migration ofthe C7 hydroxy substituent to C10, migration of the C10 oxo substituentto C9, and migration of the C9 acyloxy substituent to C7.

[0229] As shown in Reaction Scheme 13, 7-O-triethylsilyl baccatin IIIcan be converted to a tricyclic taxane through the action oftrimethyloxonium tetrafluoroborate in methylene chloride solution. Theproduct diol then reacts with lead tetraacetate to provide thecorresponding C4 ketone.

[0230] The subprocesses of Reaction scheme A can be applied at variousstages. For example, the process for the conversion of compound 30 tocompound 33 can be applied to any intermediate having a hydroxyl groupat C-10 and two hydrogens at C-9, e.g., the process for introducing C9and C10 carbonyl and hydroxyl groups can be applied to suitablyprotected intermediates 4 through 29.

[0231] Likewise, the process for introduction of C1 and C2oxygen-containing functional groups (conversion of 6 to 13 in ReactionScheme A) can be applied to any intermediate having a C3 carbonyl group.

[0232] Similarly, the process for introducing C2 and C4 acyl groups asexemplified in Reaction Schemes 6 through 10 can be applied to anyintermediate having a C1, C2 carbonate.

[0233] Also, the process for forming the oxetane ring, as exemplified inthe conversion of 24a to 27a in Reaction Scheme A, can be applied to avariety of intermediates having a C4 carbonyl group.

[0234] The aldol process exemplified in the conversion of 5 to 6 inReaction Scheme A can be applied to any suitably protected intermediatehaving a C3 carbonyl group and a C8a hydrogen. A variety of ketones oraldehydes can be used as a reactant in this process.

[0235] Formation of a cyclic carbonate from any 1,2 or 1,3 diol subunitin any intermediate can be carried out by using phosgene as a reactant.Carbonyl groups can be reduced by hydride reagents or metallic speciesto the corresponding alcohols. Alcohols can be oxidized using a varietyof oxidizing agents as exemplified in the Reaction Schemes, to thecorresponding carbonyl groups.

[0236] The compounds disclosed in this application have severalasymmetric carbons and may exist in diastereomeric, racemic, oroptically active forms. All of these forms are contemplated within thescope of this invention. More specifically, the present inventionincludes the enantiomers, diasteriomers, racemic mixtures, and othermixtures of the compounds disclosed herein.

[0237] The following examples illustrate the invention.

EXAMPLES REACTION SCHEME A

[0238] Triethylsilyloxy alcohol 3. To a solution of diol 2 (3.16 g, 13.4mmol) and DMAP (70 mg, 0.57 mmol) in CH₂Cl₂ (65 mL) at room temperaturewas added triethylamine (3.7 mL, 26.6 mmol) followed by dropwiseaddition of TESCl (2.7 mL, 16.1 mmol). After 1.75 h, the reactionmixture was diluted with 150 mL of hexane, then poured into 100 mL of asaturated aqueous NaHCO₃ solution and 150 mL of hexane. The organicphase was washed with two 100 mL portions of saturated aqueous NaHCO₃solution and with 100 mL of water, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure to give 4.88 g of crudetriethylsilyloxyalcohol 3. An analytical sample was obtained by plugfiltration through a short pad of silica gel washing with hexane andthen eluting the pure compound 3 (P₁₀=TES) (colorless oil) with 5% ethylacetate in hexane.

[0239] 3 (P₁₀=TES): ¹H NMR (300 MHz, CDCl₃) δ 0.61 (q, J=7.7 Hz, 6H, TESCH₂), 0.89 (s, 3H, CH₃ 16), 0.96 (t, J=7.7 Hz, 9H, TES CH₃), 1.03 (d,J=7.1 Hz, 3H, CH₃ 19), 1.07 (s, 3H, CH₃ 17), 1.23 (d, J=14.3 Hz, 1H,H2α), 1.56 (dd, J=6.0, 6.0 Hz, 1H, h7),.1.76 (ddd, J=5.0, 11.0, 13.7 Hz,1H, H9), 1.90 (ddd, J=2.2, 8.8, 15.4 Hz, 1H, H9), 1.96 (m, 1 H, H14α),2.37 (m, 2H, H2β, H14β), 2.51 (ddd, J=7.7, 7.7, 10.4 Hz, 1H, H8β), 2.94(s, 1H, OH-3), 4.21 (dd, J=2.2, 5.0 Hz, 1H, H10), 5.43 (dd, J=2.8, 2.8Hz, 1H, H13). ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 4.8 (TES CH₂), 6.7 (TESCH₃), 15.02 (CH₃ 19), 23.0 (CH₃ 17), 26.2 (CH₃ 18), 28.0 (CH₃ 16), 33.6(C14), 41.5 (C8), 44.2 (C2), 45.0 (C1), 45.2 (C15), 45.8 (C9), 69.6(C11), 74.9 (C10), 96.0 (C3), 123.0 (C13), 143.7 (C12); IR (CHCl₃) υ3530, 2970, 2930, 2900, 1460, 1340, 1140, 1100, 1080, 1045, 1010, 970,915, 650 cm⁻¹; MS (CI) 351 (M+1, 58), 333 (100), 219 (34).

[0240] Hydroxy Ketone 4. To a vigorously stirred solution of the crudecompound 3 (P₁₀=TES) in anhydrous CH₂Cl₂ (30 mL) at 0° C. under nitrogenwas added Ti (O^(i)Pr)₄ (13.5 mL, 43.1 mmol) followed by dropwiseaddition of anhydrous 2M ^(t)-BuOOH in hexane (18 mL, 36 mmol). After 45min dimethylsulfide (15 mL) was added slowly over a period of 5 min. Thesolution was stirred for 10 min at 0° C., then 15 min at roomtemperature and then moved to a 55° C. bath where it was heated underreflux for 8 h. The solvents were evaporated under reduced pressure, theresulting thick syrup was dissolved in ethyl acetate (850 mL) and 3.5 mLof H₂O was added dropwise with vigorous stirring. The resulting mixturewas stirred at room temperature for 1 h and then filtered through a padof Celite which was further washed with two protions of 100 mL of ethylacetate. Evaporation of the solvent under reduced pressure afforded anoil that was filtered through a short pad of silica gel eluting with 10%ethyl acetate in hexane to give 4.78 g of pure hydroxyketone 4 (P₁₀=TES)(colorless oil).

[0241] 4 (P₁₀=TES): ¹H NMR (300 MHz, CDCl₃) δ 0.58 (q, J=7.7 Hz, 6H, TESCH₂), 0.94 (t, J=7.7 Hz, 12H, CH₃ 19, TES CH₃), 0.98 (s, 3H, CH₃ 17),1.31 (s, 3H, CH₃ 16), 1.71 (dd, J=5.0, 11.5 Hz, 1H, H2α), 1.85 (m, 3H,H1, H9β, H14β), 1.96 (s, 3H, CH₃ 18), 2.15 (d, J=12.1, 1H, OH-13), 2.22(ddd, J=4.9, 13.2, 15.9 Hz, 1H, H9α), 2.56 (dddd, J=3.8, 7.1, 13.7, 13.7Hz, 1H, H8α), 2.75 (dd, J=2.2, 11.0 Hz, 1H, H2β), 2.80 (ddd, J=4.4, 7.7,11.0 Hz, 1H, H14β), 4.10 (t, J=11.0 HZ, 1H, H13β), 4.56 (d, J=5.0 Hz,1H, H10β); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 4.3 (TES CH₂), 6.5 (TES CH₃),13.4 (CH₃ 18), 18.4 (CH₃ 19), 25.8 (CH₃ 17), 27.1 (CH₃ 16), 34.7 (C14),38.2 (C15), 38.8 (C2), 44.0 (C8), 44.2 (C9), 47.8 (C1), 67.3 (C13), 69.7(C10), 137.3 (C11), 138.8 (C12), 219.2 (C3); IR (CHCl₃) υ 3550, 2960,2880, 1660, 1460, 1410, 1240, 1200, 1160, 1140, 1080, 1050, 1000, 980,900, 810 cm⁻¹; MS (CI) 367 (M+1, 2), 349 (100), 331 (55).

[0242] Ketone 5. To a solution of hydroxyketone 4 (P₁₀=TES) in anhydrouspyridine (25 mL) at −23° C. under nitrogen was added dropwise TBSOTf(3.2 mL, 13.9 mmol). After 5 min, the flask was moved to an ice bath andstirred for 1.75 h. The solution was diluted with 75 mL of hexane at 0°C. and then decanted from the insoluble oil into saturated aqueousNaHCO₃ solution (200 mL). The remaining oil was extracted with three 75mL portions of hexane. The combined organic phases were washed with two50 mL portions of saturated aqueous NaHCO₃ solution and then with 50 mLof water, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The yellowish oily residue was purified by filtration througha short pad of silica gel eluting with 10% ethyl acetate in hexane togive 4.78 g of pure ketone 5 (P₁₀=TES, P13 =TBS) (94% yield from 2).

[0243] 5 (P₁₀=TES, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 3H, TBSCH₃), 0.05 (s, 3H, TBS CH₃), 0.57 (q, J=8.2 Hz, 6H, TES CH₂), 0.93 (t,J=8.2 Hz, 9H, TES CH₃), 0.93 (s, 9H, TBS t-Bu), 0.96 (d, J=1.8 Hz, 3H,CH₃ 19), 1.06 (s, 3H, CH₃ 17), 1.33 (s, 3H, CH₃ 16), 1.68 (dd, J=5.5,11.5 Hz, 1H, H2α), 1.84 (m, 2H, H1, H9β), 1.89 (s, 3H, CH₃ 18), 1.92(dd, J=6.0, 14.3 Hz, 1H, H14α), 2.21 (ddd, J=5.5, 13.2, 15.4 Hz, 1H,H9α), 2.39 (ddd, J=8.2, 10.4, 14.3 Hz, 1H, H14β), 2.52 (ddd, J=3.9, 7.1,13.6 Hz, 1H, H8α), 2.66 (dd, J=2.8, 11.5 Hz, 1H, H2β), 4.45 (dd, J=5.5,10.4 Hz, 1H, H13β), 4.61 (d, J=5.0 Hz, 1H, H10β); ¹³C NMR δ (ppm) −5.4(TBS CH₃), −4.6 (TBS CH₃), 4.3 (TES CH₂), 6.5 (TES CH₃), 14.1 (CH₃ 18),17.9 (TBS C(CH₃)₃), 19.1 (CH₃ 19), 25.4 (CH₃ 17), 25.8 (TBS C(CH₃)₃),26.8 (CH₃ 16), 33.5 (C14), 38.6 (C15), 39.4 (C2), 43.7 (C8), 44.4 (C9),47.5 (C1), 67.5 (C13), 69.5 (C10), 136.8 (C11), 138.8 (C12), 213.5 (C3),IR (CHCl₃) υ 2950, 2900, 1680, 1460, 1420, 1395, 1365, 1250, 1200, 1110,1080, 1000, 900, 860, 840 cm⁻¹; MS (CI) 481 (M+1, 3), 463 (16), 349(100), 331 (50); Anal. Calcd. for C₂₇H₅₂O₃Si₂: C, 67.44; H, 10.90.Found: C, 67.31; H, 10.78.

[0244] Ketocarbonate 6. To a stirred solution of diisopropylamine (0.60mL, 4.28 mmol) in THF (11 mL) under nitrogen at room temperature wasadded 1.26 mL of a 3.1 M solution (3.89 mmol) of MeMgBr in ether. After3 h, a solution of ketone 5 (P₁₀=TES, P₁₃=TBS) (750 mg, 1.56 mmol) inTHF (3.5 mL) was added dropwise at room temperature. After 1.5 h, thereaction mixture was cooled to −23° C. and a solution of 4-pentenal (327mg, 3.89 mmol) in THF (4 mL) was added dropwise down the side of theflask. After 1 h, 10 mL of a saturated aqueous NH₄Cl solution was added.Ater 2 min, the reaction mixture was diluted with 100 mL of hexane, thenpoured into 100 mL of H₂O. The organic phase was washed with 100 mL ofH₂O and 100 mL of brine, and dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give 0.92 g of a yellow oil. To asolution of the crude mixture in CH₂Cl₂ (10 mL) and pyridine (10 mL)under nitrogen at −23° C. was added 2.3 mL of 4 M solution (9.36 mmol)of phosgene in toluene dropwise and the reaction mixture was warmed to−10° C. After 30 min, ethanol (3.7 mL) was added and the resultingmixture was stirred for 30 min. The reaction mixture was then dilutedwith 300 mL of hexane, washed with 200 mL of a saturated aqueous NaHCO₃solution, 200 mL of a 10% aqueous CuSO₄ solution, 200 mL of H₂O, 200 mLof a saturated aqueous NaHCO₃ solution and 200 mL of brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give 1.05 gof a yellow solid. The crude mixture was filtered through silica gelwith 10% ethyl acetate in hexanes to give 965 mg of a white solid whichwas further purified by silica gel chromatography eluting with 2% ethylacetate in hexanes to yield 745 mg (75%) of ketocarbonate 6 (P₁₀=TES,P₁₃=TBS, R=Et) as a white solid. The product was isolated as a 6:1 ratioof conformational isomers. The following NMR data is for the predominantconformer.

[0245] 6 (P₁₀=TES, P₁₃=TBS, R=Et): mp 103-104° C.; ¹H NMR (500 MHz,CDCl₃) δ 0.08 (s, 3H, TBS CH₃), 0.08 (s, 3H, TBS CH₃), 0.56 (q, J=7.8Hz, 6H, TES CH₂), 0.94 (t, J=7.8 Hz, 9H, TES CH₃), 0.96 (s, 9H, TBSt-Bu), 1.08 (s, 3H, CH₃ 17), 1.29 (m, 1H, H6), 1.38 (s, 3H, CH₃ 19),1.42 (s, 3H, CH₃ 16), 1.66 (dd, J=4.6, 12.5 Hz, 1H, H9α), 1.83 (s, 3H,CH₃ 18), 1.85 (dd, J=4.5, 4.5 Hz, 1H, H14α), 2.05 (m, 1H, H5), 2.06 (dd,J=6.4, 14.2 Hz, 1H, H5), 2.47 (m, 2H, H9α, H6), 3.01 (dd, J=3.7, 12.3Hz, 1H, H14β), 4.20 (m, 2H, H2α, H2β), 4.47 (d, J=7.3 Hz, 1H, H13β),4.50 (dd, J=4.6, 11.4 Hz, 1H, H10β), 4.91 (dd, J=1.83, 10.1 Hz, 1H,H20), 4.97 (dd, J=1.8, 16.9 Hz, 1H, H20), 5.29 (dd, J=0.9, 10.1 Hz, 1H,H7), 5.73 (dddd, J=6.9, 6.9, 10.5, 16.9 Hz, 1H, H4); ¹³C NMR δ (ppm)−5.3 (TBS CH₃), −4.5 (TBS CH₃), 4.8 (TES CH₂), 6.5 (TES CH₃), 14.0 (OEtCH₃), 15.5 (CH₃ 19), 15.9 (CH₃ 18), 18.1 (TBS C(CH₃)₃), 25.8 (TBSC(CH₃)₃), 27.6 (CH₃ 17), 28.2 (CH₃ 16), 30.4, 30.5 (C5, C6), 34.1 (C14),39.0 (C15), 41.1 (C2), 47.1 (C1), 47.5 (C9), 55.1 (C8), 63.8 (OEtCH2),66.3 (C13), 68.3 (C10), 84.0 (C7), 114.8 (C20), 134.8 (C11), 138.1(C4′), 144.9 (C12), 155.7 (Ethylcarbonate C═O), 214.8 (C3); IR (CCl₄) υ3000, 2950, 2900, 1770, 1700, 1490, 1390, 1280, 1140, 1100, 1030, 910,880, 860 cm⁻¹; MS (EI) 636 (M, 100), 593 (20), 538 (34), 409 (33); Anal.Calcd. for C₃₅H₆₄O₆Si₂: C, 65.99; H, 10.13. Found C, 65.88, H, 10.17.

[0246] Hydroxyketone 7. To a stirred solution of ketocarbonate 6(P₁₀=TES, P₁₃=TBS, R=Et) (4.00 g, 6.28 mmol) in THF (65 mL) undernitrogen at −35° C. was added 50 mL of a 0.2 M solution (10 mmol) of LDAin THF down the side of the flask over a 10 min period. After 30 min,the reaction mixture was cooled to −78° C. and 2.29 g of(R)-camphorylsulfonyl oxaziridine (10 mmol) in THF (18 mL) was addeddropwise down the side of the flask. After 30 min, the reacion mixturewas quenched with 300 mL of a saturated aqueous NaHCO₃ solution andextracted with 500 mL and then 150 mL of 25% ethyl acetate in hexanes.The combined organic phases were washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to yield 7 g of a waxysolid. This material was purified by flash chromatography, eluting with3% ethyl acetate in hexanes to yield 3.50 g of hydroxyketone 7 (P₁₀=TES,P₁₃=TBS, R=Et) (85%).

[0247] 7 (P₁₀=TES, P₁₃=TBS, R=Et): ¹H NMR (500 MHz, CDCl₃) δ 0.01 (s,3H, TBS CH ₃), 0.03 (s, 3H, TBS CH₃), 0.50 (q, J=7.8 Hz, 6H, TES CH₂),0.87 (t, J=7.8 Hz, 9H, TES CH₃), 0.90 (s, 9H, TBS t-Bu), 1.03 (s, 3H,CH₃ 17), 1.25 (t, J=7.0 Hz, 3H, OEt CH₃), 1.35 (s, 3H, CH₃ 19), 1.40 (m,1H, H6), 1.41 (s, 3H, CH₃ 16), 1.66 (dd, J=4.6, 12.8 Hz, 1H, H9β), 1.77(d, J=1.4 Hz, 3H, CH₃ 18), 1.83 (dd, J=6.0, 14.7 Hz, 1H, H14α), 1.97(dd, J=4.1, 8.5 Hz, 1H, H1), 2.02 (m, 2H, H5, H5), 2.44 (dd, J=11.9,11.9 Hz, 1H, H9α), 2.75 (d, J=10.5 Hz, 1H, OH−2), 4.14 (q, J=14.2 Hz,2H, OEt CH₂), 4.35 (dd, J=6.0, 8.7 Hz, 1H, H13), 4.42 (dd, J=4.6, 11.0Hz, 1H, H10), 4.49 (dd, J=4.1, 10.1 Hz, 1H, H2), 4.86 (dd, J=1.8, 10.3Hz, 1H, H20), 4.92 (dd, J=1.8, 16.9 Hz, 1H, H20), 5.23 (dd, J=1.4, 10.1Hz, 1H, H7), 5.67 (dddd, J=6.9, 6.9, 10.5, 16.9 Hz, 1H, H4); ¹³C NMR δ(ppm) −5.3 (TBS CH₃), −4.5 (TBS CH₃), 4.7 (TES CH₂), 6.5 (TES CH₃), 14.0(OEt CH₃), 15.0 (CH₃ 19), 16.0 (CH₃ 18), 18.0 (TBS C(CH₃)₃), 25.8 (TBSC(CH₃)₃), 27.5, 27.8 (CH₃ 17), 28.1 (CH₃ 16), 30.4, 30.5 (C5, C6), 36.9(C15), 47.3 (C9), 54.5 (C1), 54.7 (C8), 63.9 (OEt CH₂), 66.2 (C13), 67.8(C10), 70.3 (C2), 83.6 (C7), 114.9 (C20), 135.4(C11), 137.9 (C4′), 144.5(C12), 155.6 (Ethylcarbonate C═O), 217.8 (C3); IR (CCl₄) υ 3600, 2950,2900, 1750, 1700, 1660, 1470, 1400, 1370, 1240, 1080, 1050, 1000, 840,680 cm⁻¹; MS (CI) 653 (M+1, 8), 564 (100), 431 (69), 389 (67).

[0248] Hydroxycarbonate 8. To a vigorously stirred solution ofhydroxyketone 7 (P₁₀=TES, P₁₃=TBS, R=Et) (2.69 g, 4.12 mmol) in toluene(117 mL) under nitrogen at −78° C. was added dropwise down the side ofthe flask 85 mL of a 0.97 M solution (82.4 mmol) of RedAl in toluene.After 6 h at −78° C., the solution was allowed to gradually warm to roomtemperature over a period of 6 h. The mixture was recooled to −10° C.and 125 mL of a 2 M solution (250 mmol) of acetic acid in THF was addeddropwise down the side of the flask. The cloudy mixture was stirred 10min then poured into 1200 mL of 50% ethyl acetate in hexanes and washedwith 1 L of a saturated aqueous NaHCO₃ solution. The aqueous phase wasextracted with four 500 mL portions of ethyl acetate and the combinedorganic phases were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to yield 2.29 g of 2,3,7-triol as awhite solid. This material was used without further purification.

[0249] To a vigorously stirred solution of triol (2.29 g, 3.93 mmol) inCH₂Cl₂ (157 mL) and pyridine (15.7 mL) under nitrogen at −78° C. wasquickly added 7.6 mL of a 3.0 M solution (23 mmol) of phosgene intoluene. The solution was allowed to warm to room temperature over aperiod of 1 h then poured into 250 mL of ethyl acetate, washed with two125 mL portions of a saturated aqueous NaHCO₃ solution and 100 mL brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toyield 2.52 g yellow oil. This material was filtered through a 2 inch padof silica gel with 50% ethyl acetate in hexanes and concentration underreduced pressure yielded 2.39 g (95% from 7) of hydroxy carbonate 8(P₁₀=TES, P₁₃=TBS) as a white solid.

[0250] 8 (P₁₀=TES, P₁₃=TBS): mp 155-157° C.; ¹H NMR (500 MHz, CDCl₃) δ0.09 (s, 3 H, TBS CH₃), 0.10 (s, 3H, TBS CH₃), 0.59 (q, J=8.2 Hz, 6H,TES CH₂), 0.96 (t, J=8.2 Hz, 9H, TES CH₃), 0.97 (s, 9H, TBS t-Bu), 1.11(s, 3H, CH₃ 19), 1.14 (s, 3H, CH₃ 17), 13.0 (s, 3H, CH₃ 16), 1.39 (dd,J=4.1, 13.3 Hz, 1H, H9β), 1.65 (m, 2H, H6, H6), 1.99 (dd, J=6.4, 15.1Hz, 1H, H14α), 2.01 (d, J=0.9 Hz, 3H, CH₃ 18), 2.04 (d, J=3.7 Hz, 1H,H1), 2.11 (ddd, J=7.8, 15.6, 15.6 Hz, 1H, H5), 2.28 (ddd, J=9.6, 9.6,14.2 Hz, 1H, H14,β), 2.34 (dd, J=12.4, 13.3 Hz, 1H, H9β), 2.41 (m, 1H,H5), 3.87 (dd, J=0.9, 10.5 Hz, 1H, H7), 3.95 (d, J=3.7 Hz, 1H, H2), 4.59(dd, J=3.7, 11.4 Hz, 1H, H10β), 4.40 (s, 1H, H3), 4.55 (dd, J=6.4, 8.7Hz, 1H, H13), 5.03 (d, J=10.5 Hz, 1H, H20), 5.07 (dd, J=1.5, 17.0 Hz,1H, H20), 5.77 (m, 1H, H4); ¹³C NMR δ (ppm) −5.4 (TBS CH₃), −4.4 (TBSCH₃), 4.8 (TES CH₂), 6.5 (TES CH₃), 15.5 (CH₃ 18), 17.9 (TBS C(CH₃)₃),18.2 (CH₃ 19 ), 25.6 (TBS C(CH₃)₃), 25.9 (CH₃ 16), 27.5 (CH₃ 17), 28.3(C6), 28.4 (C5), 29.8 (C14), 30.8 (C15), 36.5 (C8), 36.8 (C9), 37.3,50.8 (C1), 66.6 (C10), 67.8 (C13), 70.5 (C2 91.9 (C3), 91.9 (C7), 116.3(C20), 133.7 (C11), 137.9 (C4′), 142.6 (C12), 148.0 (cyclic carbonateC═O); IR (CCl₄) υ 3450, 2950, 2870, 1750, 1460, 1380, 1350, 1220, 1120,1080, 1040, 980, 900, 820, 710cm⁻¹; MS (CI) 625 (M+1−H₂O, 6), 551 (11),477 (100), 459(12), 433 (8), 344 (90); Anal. Calcd. for C₃₃H₆₀O₆Si₂: C,64.92; H, 9.90; Found: C, 65.13; H, 9.88.

[0251] Ketocarbonate 9. To a vigorously stirred solution ofdimethylsulfoxide (2.41 mL, 34 mmol) in CH₂Cl₂ (57 mL) under nitrogen at−78° C. was added 8.5 mL of a 2.0 M solution (17.0 mmol) of oxalylchloride in CH₂Cl₂. After 10 min, a solution of hyroxycarbonate 8(P₁₀=TES, P13=TBS) (3.45 g, 5.67 mmol) in 16 mL CH₂Cl₂ was addeddropwise down the side of the flask. After 30 min at −78° C.,triethylamine (6.8 mL, 49 mmol) was added and the mixture was warmed toroom temperature. The mixture was diluted with 200 mL hexanes, washedwith two 75 mL portions of a saturated aqueous NaHCO₃ solution andbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to yield 3.45 g of a yellow solid. This material was filteredthough a 1 inch pad of silica gel with 10% ethyl acetate in hexanes andthen recrystallized from hexanes to yield 2.62 g of ketocarbonate 9 aswhite crystals. The mother liquor was purified by silica gelchromatography, eluting with 10% ethyl acetate in hexanes and thenrecrystallization from hexanes to yield an additional 0.58 g ofketocarbonate 9 (P₁₀=TES, P 3 =TBS) (total yield: 3.20 g, 93%).

[0252] 9 (P₁₀=TES, P₁₃=TBS): mp 140.0-141.5° C.; ¹H NMR(500 MHz,CDCl₃) δ0.11 (s, 3H, TBS CH₃), 0.12 (s, 3H, TBS CH₃), 0.60 (q, J=7.8 Hz, 6H, TESCH₂), 0.96 (t, J=7.8 Hz, 9H, TES CH₃), 0.98 (s, 9H, TBS t-Bu), 1.06 (s,3H, CH₃ 19), 1.17 (s, 6H, CH₃ 16, CH₃ 19), 1.42 (dd, J=3.7, 14.2 Hz, 1H,H9β), 1.63 (m, 2H, H6, H6), 2.12 (m, 1H, H5), 2.38 (d, j=0.9 Hz, 3H, CH₃18), 2.47 (dd, J=11.4, 13.3 Hz, 1H, H9α), 2.65 (d, J=8.2, 1 H, H1), 3.94(dd, J=1.4, 10.4 Hz, 1H, H7), 4.44 (dd, J=3.7, 11.4 Hz, 1H, H10), 4.49(s, 1H, H3), 4.64 dd, J=6.9, 7.8 Hz, 1H, H13), 5.04 (dd, J=1.4, 11.9 Hz,1H, H20), 5.07 (dd, J=1.8, 17.4 Hz, 1H, H20), 5.76 (m, 1H, H4); ¹³C NMRδ (ppm) −5.4 (TBS CH₃),−4.5 (TBS CH₃), 4.8 (TES CH₂), 6.5 (TES CH₃),15.7 (CH₃ 18), 17.8 (CH₃ 19), 17.9 (TBS C(CH₃)₃), 25.5 (TBS C(CH₃)₃),28.2 (CH₃ 16), 28.3 (CH₃ 17), 28.3 (C6), 29.6 (C5), 30.4 (C14), 3.77(C15), 38.0 (C8, C9), 62.1 (C1), 66.5 (C10), 67.5 (C13), 91.3 (C3), 91.5(C7), 116.4 (C20), 132.8 (C11), 137.0 (C4′), 145.4 (C12), 146.6 (cycliccarbonate C═O), 206.8 (C2); IR (CCl₄) υ 2930, 2860, 1760, 1670, 1450,1380, 1340, 1240, 1180, 1170, 1120, 1090, 1060, 1040, 980, 890, 860,820, 700, 650 cm⁻¹; MS (CI) 607 (M+1, 6), 549 (11), 475 (100), 431 (4),347 (45); Anal. Calcd. for C₃₃H₅₈O₆Si₂: C, 65.30; H, 9.63; Found: C,65.23; H, 9.66.

[0253]2-Keto-3-Hydroxy-Lactone 10. To a stirred solution of 3,7-cycliccarbonate 9 (P₁₀=TES, P₁₃=TBS) (2.246 g, 3.70 mmol) in THF (9 mL) wasadded 19.4 mL of 0.2 M LTMP (3.88 mmol) in THF dropwise down the sidesof the flask at −25° C. The reaction mixture was allowed to warm to −10°C. over the course of 30 min. The cold reaction mixture was poured into100 mL of 10% aqueous acetic acid and extracted with 100 mL of 10 %ethyl acetate in hexanes. The organic phase was washed with 50 mL of asaturated aqueoues NaHCO₃ solution and 50 mL of brine. The combinedaqueous phases were extracted with two 20 mL portions of 10% ethylacetate in hexanes. The oraganic phases were combined, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give 2.4 gof a yellow oil. This material was purified by silica gelchromatography, eluting with 5% then 10% ethyl acetate in hexanes toyield 2.033 g (90%) of the hydroxy lactone 10 (P₁₀=TES, P₁₃=TBS) as afoamy solid and 0.207 g (7.2%) of the 3-carbamate.

[0254] 10 (P₁₀=TES, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃) δ 0.12 (s, 3H, TBSCH₃), 0.14 (s, 3H, TBS CH₃), 0.61 (q, J=7.8 Hz, 6H, TES CH₂), 0.92 (s,9H, TBS t-Bu), 0.97 (t, J =7.8 Hz, 9H, TES CH₃), 1.11 (s, 3H, CH₃ 17),1.22 (s, 3H, CH₃ 19), 1.27 (s, 3H, CH₃ 16), 1.32 (dd, J=3.2, 13.3 Hz,1H, H9β), 1.64 (ddd, J=2.3, 6.9, 9.2 Hz, 1H, H6), 2.07 (m, 2H, H6, H5),2.17 (m, 1H, H14α), 2.33 (m, 1H, H5), 2.65 (m, 2H, H14β, H1), 2.74(dd,J=12.4, 12.4 Hz, 1H, H9α), 3.92 (dd, J=2.8, 11.5 Hz, 1H, H7), 4.47(dd, J=3.2, 11.0 Hz, 1H, H10), 4.55 (dd, J=2.8, 9.6 Hz, 1H, H13), 5.02(d, J=10.1 Hz, 1H, H20), 5.07 (dd, J=1.4, 16.9 Hz, 1H, H20), 5.81 (dddd,J=6.9, 6.9, 10.5, 16.9 Hz, 1H, H4); ¹³C NMR δ (ppm) −5.2 (TBS CH₃), −4.5(TBS CH₃), 4.8 (TES CH₂), 6.6 (TES CH₃), 16.4 (CH₃ 18) 17.9 (TBSC(CH₃)₃), 24.2 (CH₃ 19), 25.7 (TBS C(CH₃)₃), 26.9 (CH₃ 16), 30.1 (CH₃17), 30.4 (C5), 32.7 (C6), 32.9 (C14), 39.1 (C15), 40.6 (C9), 48.1 (C8),62.0 (C1), 67.3 (C10), 67.6 (C13), 87.9 (C3), 91.1 (C7), 115.8 (C20),137.7 (C11), 138.5 (C4′), 143.0 (C12), 173.5 (C4), 207.6 (C2); IR (CCl₄)υ 3500, 2970, 2900, 1780, 1700, 1480, 1360, 1260, 1210, 1160, 1070,1010, 910, 890, 840 cm⁻¹; MS (EI) 606 (M, 100), 549 (69), 474 (27), 431(65), 417(40; Anal. Calcd. for C₃₃H₅₈O₆Si₂: C, 65.30; H, 9.63; Found: C,65.38; H, 9.64.

[0255] Keto Lactone 11. To the 2-keto-3-hydroxylactone 10 (P₁₀=TES,P₁₃=TBS) (1.10 g, 1.83 mmol) was added a 0.1 M solution of SmI₂ in THF(82 mL, 8.2 mmol). The resulting dark blue solution was stirred at roomtemperature under N₂ for 4h. After cooling to 0° C. an ethereal solutionof HCl (0.66M; 4.2 mL, 2.77 mmol) was added; after 5 min the flask wasopened to the air and the reaction mixture was diluted with 200 mL ofcold ethyl acetate, then poured into 50 mL of ice cold 0.2N aqueous HCl.The organic phase was separated and washed with 50 mL of a 5% aqueouscitric acid solution, two 50 mL portions of a saturated aqueous NaHCO₃solution and 50 mL of brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting material wasdissolved in 100 mL of hexanes, then silica gel (230-400 mesh; 4.3 g)was added and the mixture was vigorously stirred at room temperature for65 min before filtering through a 1 inch pad of silica gel eluting with300 mL of 20% ethyl acetate in hexanes. The solvent was evaporated underreduced pressure and the residue was purified by silica gelchromatography, eluting with 10% ethyl acetate in hexanes to yield 822mg (77%) of the cis-kotelactone 11 and 164 mg (15%) of the correspondingtrans isomer.

[0256] To a solution of the trans-2-ketolactone (611 mg, 1.03 mmol)stirred in 10 mL of TBF under nitrogen at 0° C. was added down the sideof the flask 6.8 mBuOKL of a 0.6 M solution (4.1 mmol) of t-in THF. Theresulting solution was stirred for 1.5 h then 10 mL of a 10% acetic acidsolution in THF was added down the side of the flask. After stirring for5 min the mixture was diluted with 200 mL of hexanes and poured into 100mL of a saturated aqueous NaHCO₃ solution. The organic layer was washedwith water and brine then dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to yield 615 mg of pale brown oil. The oil wasdissolved in 10 mL of hexanes and silica gel (3.0 g) was added. Themixture was stirred vigorously for 15 min then filtered through a ½ inplug of silica gel with 20% ethyl acetate in hexanes. Concentration ofthe filtrate under reduced pressure yielded 576 mg of pale yellow oil.This material was purified by silica gel chromatography, eluting with10% then 20% ethyl acetate in hexanes to yield 472 mg (77%) of purecis-2-ketolactone 11 (P₁₀=TES, P₁₃=TBS), 84 mg (13%) of pure transisomer and 24 mg of a 6:1 mixture of cis:trans isomers.

[0257] 11 (P₁₀=TES, P₁₃=TBS): mp=86.5-88.0° C.; ¹H NMR (500 MHz, CDCl₃)δ 0.05 (s, 3H, TBS CH₃), 0.07 (s, 3H, TBS CH₃), 0.54 (q, J=7.8 Hz, 6H,TES CH₂), 0.84 (s, 9H, TBS t-Bu), 0.90 (t, J=7.8 Hz, 9H, TES CH₃), 1.03(s, 3H, CH₃ 17), 1.11 (s, 3H, CH₃ 16), 1.15 (s, 3H, CH₃ 19), 1.35 (dddd,J=4.6, 4.6, 7.3, 14.2 Hz, 1H, H6), 1.43 (dd, J=3.7, 12.8 Hz, 1H, H9β,),1.67 (dddd, J=3.2, 7.3, 10.1, 13.7 Hz, 1H, H6), 1.83 (dd, J=4.6, 16.0Hz, 1H, H14α), 2.03 (m, 1H, H5), 2.07 (d, J=1.4 Hz, 3H, CH₃ 18),,2.25(m, 1H, H5), 2.30 (dd, J=11.9, 12.3 Hz, 1H, H9α), 2.45 (d, J=8.2 Hz, 1H,H1), 2.58 (ddd, J=8.7, 9.2, 16.0 Hz, 1H, H14β), 3.93 (dd, J=2.8, 11.4Hz, 1H H7β), 4.03 (s, 1H, H3α), 4.37 (dd, J=3.7, 11.0 Hz, 1H, H10β),4.46 (ddd, J=1.4, 4.6, 9.2 Hz, 1H, H13β), 4.96 (dd, J=1.4, 10.1 Hz, 1H,H20), 5.01 (dd, J=1.4, 17.4 Hz, 1H, H20), 5.73 (dddd, J=6.4, 7.3, 10.5,16.9 Hz, 1H, H4); ¹³C NMR δ (ppm) −5.3 (TBS CH₃), −4.6 (TBS CH₃), 4.5(TES CH₂), 6.5 (TES CH₃), 15.0 (CH₃ 18), 18.0 (TBS C(CH₃)₃), 25.7 (TBSC(CH₃)₃), 28.9 (CH₃ 19), 29.2 (CH₃ 16), 29.8 (C5), 29.9 (CH₃ 17), 30.3(C6), 32.8 (C14), 38.5 (C15), 44.2 (C8), 44.9 (C9), 60.6 (C3), 61.2(C1), 66.9 (C10), 67.8 (C13), 91.9 (C7), 115.7 (C20), 137.7 (C11), 138.5(C4′), 142.4 (C12), 174.7 (C4), 204.8 (C2); IR (CCI₄) υ 2975, 2899,1780, 1705, 1460, 1355, 1260, 1180, 1070, 1060, 1000, 830 cm⁻¹; MS (CI)591 (M+1, 5), 523 (6), 459(100), 441(5); Anal. Calcd. for C₃₃H₅₈O₅Si₂:C, 66.07; H, 9.89; Found: C, 66.97; H, 9.91.

[0258]1-Hydroxy-2-Keto-Lactone 12. To 34.2 mL of a stirred 0.2 Msolution (6.84 mmol) of LTMP in THF under nitrogen at −10° C. was addeda solution of ketolactone 11 I(P₁₀=TES, P₁₃=TBS) (1.008 g, 1.71 mmol) in10 mL of THF dropwise down the side of the flask. After 0.5 h, thereaction mixture was cooled to −40° C. and a solution of(±)-camphorsulfonyl oxaziridine (1.96 g, 8.55 mmol) in THF (10 mL) wasadded dropwise down the side of the flask. After 20 min, the reactionmixture was cooled to −78° C., diluted with 200 mL of hexanes andrapidly poured into 250 mL of a vigorously stirred saturated aqueousNH₄Cl solution. The aqueous phase was extracted with two 50 mL portionsof hexane and the combined organic phase were dried over anhydrousNa₂SO₄ and concetrated under reduced pressure to give 1.4 g of a waxysolid. This material was chromatographed (CH₂Cl₂ followed by hexanesincreasing to 10% ethyl acetate in hexanes) to give 0.882 g ofhydroxyketolactone 12 (P₁₀=TES, P₁₃=TBS) (85%) as a white solid, 0.083 gof the corresponding trans-hydroxyketolactone (8%) as a solid, and 31 mgof returned ketolactone 11 (3%).

[0259] 12 (P₁₀=TES, P₁₃=TBS): mp 124-126° C.; 1H NMR (C₆D₆) δ (ppm) 0.09(s, 3H, CH₃ in TBDMS), 0.17 (s, 3H, CH₃ in TBDMS), 0.62 (q, J=7.78 Hz,6H CH₂'s in TES), 1.03 (t, J=7.78, 9H CH₃'s in TES), 1.05 (s, 3H,CH₃19), 1.13 (s, 9H, t-Bu in TBS), 1.20 (s, 3 H, CH₃17), 1.39 (m, 1H,H6), 1.42 (s, 3H, CH₃ 16), 1.44 (dd, J=0.92, 13.28 Hz, 1H, H9β), 1.98(dd, J=9.61, 12.82 Hz, 1H, H14β), 2.05 (m, 1H, H5), 2.06 (broad, 1H,OH1, D2O exchangable), 2.25 (m, 1H, H6), 2.27 (d, J=0.91 Hz, 3H, CH₃18),2.29 (m, 1H, H5), 2.41 (dd, J=10.98, 13.28 Hz, 1H, H9α), 2.56 (dd,J=3.21, 12.82 Hz, 1H, H14α), 3.83 (dd, J=2.75, 11.90 Hz, 1H, H7), 4.04(s, 1H, H3), 4.47 (dd, J=0.92, 10.98 Hz, 1H, H10 ), 4.60 (ddq, J=0.91,3.21, 9.61 Hz, 1H, H13), 5.11 (br d, J=10.53 Hz, 1H, H20), 5.18 )br d,J=17.40 Hz, 1H, H20), 5.77 (m, 1H, H4); 13C NMR (CDCl₃) δ (ppm) −5.4(TBS CH₃), −4.7 (TBS CH₃), 4.5 (TES CH₂), 6.5 (TES CH₃), 15.5 (CH₃ 18),17.9 (TBS C(CH₃)₃), 22.5 (CH₃ 19), 25.7 (TBS C(CH₃)₃), 26.3 (CH₃ 16),29.8 (CH₃ 17), 29.8 (C5), 30.4 (C6), 39.6 (C14), 41.3 (C15), 44.5 (C9),45.0 (C8), 58.1 (C3), 66.5 (C10), 68.2 (C13), 83.0 (C1), 91.7 (C7),115.7 (C20), 137.0 (C11), 137.6 (C4′), 145.5 (C12), 175.0 (C4), 202.4(C2); IR (CCl₄) υ 3500, 3000, 1780, 1720, 1100 cm⁻¹; MS (CI) 607 (M+1,10), 589 (56), 475 (100), 457 (61); Anal. Calcd for C₃₃H₅₈O₆Si₂: C,65.30; H, 9.63. Found: C, 65.19; H, 9.60.

[0260] 1,2-Dihydroxy-trans-lactone 13. To a stirred 1.23 M solution ofRed-Al (4.6 mmol, 5.6 mmol) in THF under nitrogen at −78° C. was quicklyadded a solution of cis-hydroxyketone 12 (P₁₀=TES, P₁₃=TBS) (342 mg,0.563 mmol) in THF (25 mL). After 1.5 h, 25 mL of a 15% aqueous NaOHsolution was added dropwise directly to the reaction mixture. Thereaction mixture was vigorously stirred at room temperature for 3 h andwas then poured into 100 mL of H₂O and extracted with two 100 mLportions of ether. The organic phases were combined and washed with 100mL of H₂O and 100 mL of brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give 0.35 g of a pale yellowsolid. This material was purified by silica gel chromatography elutingwith 10% ether in hexanes followed by 25% ethyl acetate in hexanes toyield 290 mg trans-diol 13 as colorless needles, 14.5 mg (4.2 %) oftrans-hydroxyketone, and 20 mg of a mixture of cis-diol and unknownbyproducts. To a solution of the mixture containing cis-diol in THF (1mL) under nitrogen at room temperature was added 0.5 mL a 30% aqueoussolution of NaOH. After 2.5 h, the reaction mixture was poured into 30mL of H₂O and extracted with 30 mL of ether. The organic phase waswashed with 30 mL of H₂O and 30 mL of brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure to give 0.02 g of a yellowsolid, which was purified by silica gel chromatography eluting with 5%ethyl acetate in hexanes to yield an additional 12 mg (total yield: 302mg, 88%) of trarn-diol 13 (P₁₀=TES, P₁₃=TBS).

[0261] 13 (P₁₀=TES, P₁₃=TBS): mp 127-128° C., ¹H NMR (500 MHz, CDCl₃) δ0.09 (s, 3H, TBS CH₃), 0.11 (s, 3H, TBS CH₃), 0.60 (q, J=8.1 Hz, 6H, TESCH₂), 0.87 (s, 9H, TBS t-Bu), 0.96 (t, J=8.1 Hz, 9H, TES CH₃) 1.13 (s,3H, CH₃ 17), 1.23 (s, 3H, CH₃ 16), 1.31 )s, 3H, CH₃ 19), 1.42 (dd,J=3.7, 12.8 Hz, 1H, H9β), 1.46 (ddd, J=4.8, 8.8, 11.4 Hz, 1 1H, H6),1.74 (dddd, J=3.3, 7.3, 9.9, 12.4 Hz, 1H, H6), 1.99 (d, J=1.5 Hz, 3H,CH₃ 18), 2.10 (m, 1H, H5), 2.21 (dd, J=3.7, 5.4 Hz, 1H, H14α), 2.26 (m,3H, H5, H9α, H14β), 2.92 (d, J=7.7 Hz, 1H, H3), 3.84 (dd, J=2.2, 7.7 Hz,1H, H2), 3.85 (s, 1H, OH1), 3.97 (dd, J=2.9, 11.4 Hz, 1H, H7), 4.47 (dd,J=3.7, 11.4 Hz, 2H, H13, H10), 5.01 (dd, J=1.8, 12.2 Hz, 1H, H20), 5.07(dd, J=1.7, 17.0 Hz, 1H, H20), 5.78 (dddd, J=7.3, 7.3, 10.1 16.5 Hz, 1H,H4), 6.87 (d, J=2.9 Hz, 1H, OH2), ¹³C NMR (CDCl₃) δ (ppm) −5.31, −4.59,4.79, 6.55, 16.60, 17.68, 21.24, 24.70, 25.62, 28.50, 29.52, 30.05,40.20, 40.41, 44.18, 45.18, 45.60, 66.62, 69.25, 71.32, 88.91, 116.09,136.96, 138.63, 139.93, 180.10, IR (CHCl₃) υ 3050, 1730, 1460, 1350cm⁻¹, MS (EI) 608 (M, 13), 590 (26), 267 (100), Anal. Calcd. forC₃₃H₆₀O₆Si₂: C, 65.08; H, 9.92. Found C, 65.06; H, 9.98.

[0262] Carbonate 14. To a stirred solution of diol 13 (P₁₀=TES, P₁₃=TBS)(1.00 g, 1.64 mmol) in CH₂Cl₂ (58 mL) and pyridine (5.8 mL) undernitrogen at −78° C. was added dropwise 8.2 mL of 2 M solution (16.4mmol) of phosgene in toluene. Then the reaction mixure was warmed to−23° C. and stirred for 30 min. To the resulting mixture, 50 mL of asaturated aqueous NaHCO₃ solution was added. After warming to roomtemperature for 10 min, the reaction mixture was extracted with 200 mLof 10% ethyl acetate in hexanes. The organic phase was washed with 100mL of a 10% aqueous CuSO₄ solution, two 200 mL portions of a saturatedaqueous NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give 1.1 g of a pale yellowsolid. This material was filtered through a 3 inch pad of silica gelwith 15% ethyl acetate in hexanes to yield 1.045 g (100%) of carbonate14 (P₁₀=TES, P₁₃=TBS) as a white solid.

[0263] 14 (P₁₀=TES, P₁₃=TBS): mp 146-147° C., ¹H NMR (500 MHz, CDCl₃) δ0.11 (s, 3H, TBS CH₃), 0.12 (s, 3H, TBS CH₃), 0.61 (q, J=7.8 Hz, 6H, TESCH₂), 0.88 (s, 9H, TBS t-Bu), 0.96 (t, J=7.8 Hz, 9H TES CH₃), 1.20 (s,3H, CH₃ 17), 1.30 (s, 3H, CH₃ 16 ), 1.32 (s, 3H, CH₃ 19), 1.40 (ddd,J=2.7, 4.5, 9.2 Hz, 1H, H6), 1.44 (d, J=3.7, 13.3 Hz, 1H, H9β), 171(dddd, J=2.7, 6.9, 9.6, 12.8 Hz, 1H, H6), 2.11 (ddd, J=7.8, 15.3, 15.3Hz, 1H, H5), 2.29 (dd, J=3.2, 15.6 Hz, 1H, H14α), 2.31 (m, 2H, H5, H9α),2.59 (dd, J=9.2, 15.6 Hz, 1H, H14β), 2.99 (d, J=7.3 Hz, 1H, H3α), 4.02(dd, J=2.7, 11.4 Hz, 1H, H7β), 4.38 (dd, J=3.7, 11.0 Hz, 1H, H10β), 4.47(d, J=7.3 Hz, 1H, H2β), 4.57 (dd, J=2.1, 9.2 Hz, 1H, H13β), 5.02 (dd,J=1.4, 10.1 Hz, 1H, H20), 5.06 (dd, J=1.4, 16.9 Hz, 1H, H20), 5.77(dddd, J=6.9, 6.9, 10.1, 17.0 Hz, 1H, H4), ¹³C NMR (CDCl₃) δ (ppm)−5.37, −4.60, 4.75, 6.51, 17.02, 17.60, 21.24, 24.64, 25.55, 27.36,29.50, 30.11, 37.56, 39.96, 42.89, 43.75, 45.39, 66.54, 68.29, 87.37,90.05, 116.15, 136.54, 136.94, 144.93, 153.32, 169.89, IR (CHCl₃) υ3070, 1800 cm⁻¹. MS (EI) 634 (M, 12), 577 (100), Anal. Calcd. forC₃₄H₅₈O₇Si₂: C, 64.31; H, 9.21. Found C, 64.41; H, 9.22.

[0264] Ketoester 15. To a stirred solution of lactone 14 (P₁₀=TES,P₁₃=TBS) (1.05 g, 1.65 mmol) in methanol (70 mL) under nitrogen at −78°C. was added a saturated solution of ozone in methylene chloride (50 mL,40 mL then 8 mL) until no more starting material remained by TLCanalysis. Triethylamine (4.8 mL) and trimethylphosphite (3.1 mL) wereadded sequentially to the resulting mixture at −78° C. After stirring 5min, the solution was warmed to 0° C. and stirred for 2 h. The resultingsolution was poured into 250 mL of a saturated aqueous NaHCO₃ solutionand extacted with three 200 mL portions of CH₂Cl₂. The combined organiclayers were washed with 150 mL of a saturated NaHCO₃ solution, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to give1.10 g of the aldehyde as a colorless oil. This material was usedfurther purification.

[0265] To a stirred solution of the aldehyde (1.10 g) in t-butanol (30.8mL), acetone (10.3 mL) and 8 mL of a 1.25 M (10 mmol) aqueous KH₂PO₄solution at 0° C. was added 11.3 mL of a 1 M (11.3 mmol) aqueous KMnO₄solution over the course of 2 min. The reaction mixture was stirred at0° C. for 30 min, poured into 200 mL of a 10% aqueous Na₂S₂)₃ solutionand extracted with three 200 mL portions of ethyl acetate. The combinedorganic layers were washed with 50 mL of water, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. To a stirred solution ofthe oily residue in ether (30 mL) at room temperature was added anethereal solution of CH₂N₂ (20 mL). The solution was concentrated underreduced pressure to give 1.15 g of a colorless oil. This material wasfiltered through a 2 inch pad of silica gel with 40% ethyl acetate inhexanes and concentration under reduced pressure yielded 1.01 g (91%) oflactone ester 15 (P₁₀=TES, P₁₃=TBS, R=Me).

[0266] 15 (P₁₀=TES, P₁₃=TBS, R=Me): ¹H NMR (500 MHz, CDCl₃) δ 0.12 (s,3H, TBS CH₃), 0.12 (s, 3H, TBS CH₃), 0.60 (q, J=8.1 Hz, 6H, TES CH₂),0.88 (s, 9H, TBS t-Bu), 0.96 (t, J=8.1 Hz, 9H, TES CH₃), 1.21 (s, 3H,CH₃), 1.30 (s, 3H, CH₃), 1.33 (s, 3H, CH₃), 151 (dd, J=3.7, 13.2 Hz, 1H,H9β), 1.53 (m, 1H, H6), 2.06 (d, J=1.1 Hz, 3H, CH₃ 18), 2.07 (ddd,J=2.9, 7.7, 21.6 Hz, 1H, H6), 2.29 (dd, J=3.7, 15.8 Hz, 1H, H14α), 2.31(dd, J=13.2, 13.2 Hz, 1H, H9α), 2.46 (ddd, J=7.7, 16.8, 24.5 Hz, 1H,H5), 2.53 (ddd, J=5.5, 7.7, 16.8 Hz, 1H, H5), 2.60 (dd, J=9.2, 15.8 Hz,1H, H14β), 2.99 (d, J=7.3 Hz, 1H, H3α), 3.68 (s, 3H, CO₂Me), 4.09 (dd,J=2.6, 12.1 Hz, 1H, H7β), 4.39 (dd, J=3.7, 11.0 Hz, 1H, H10β), 4.47 (d,J=7.3 Hz, 1H, H2β), 4.59 (dd, J=1.8, 9.2 Hz, 1H, H13β); Anal. Calcd, forC₃₄H₅₈O₉Si₂: C, 61.22; H, 8.77. Found C, 61.30; H, 8.79.

[0267] Enol ester 16. To a stirred solution of lactone ester 15(P₁₀=TES, P₁₃=TBS, R=Me) (1.01 g, 1.51 mmol) in THF (24.5 mL) at −78° C.was added slowly a 19.4 mL of a 0.2 M solution (3.88 mmol) of LDA in THFdown the side of the flask over the course of 3 min. After stirring 35min, 10 mL of a 33% solution of acetic acid in THF was quickly added.After 5 min, the mixture was poured into 150 mL of a saturated aqueousNaHCO₃ solution and extracted with three 200 mL portions of CHCl₃. Thecombined organic phases were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give 1.02 g of crude enol ester16 (P₁₀=TES, P₁₃=TBS, R=Me) as a colorless oil. Approximately 3% ofunreacted ester lactone 15 was still present but this material was usedwithout further purification.

[0268] 16 (P₁₀=TES, P₁₃=TBS, R=Me): ¹H NMR (300 MHz, CDCl₃) δ 0.09 (s,3H, TBS CH₃), 0.10 (s, 3H, TBS CH₃), 0.61 (q, 6H, TES CH₂), 0.87 (s, 9H,TBS t-Bu), 0.96 (t, J=8.0 Hz, TES CH₃), 1.08 (s, 3H, CH₃), 1.21 (s, 3H,CH₃), 1.33 (S, 3H, CH₃), 1.61 (d, J=4.3 Hz, 1H, OH-7), 1.89 (dd, J=4.3,13.9 Hz, 1H, H9α), 1.95 (dd, J=11.2, 11.2 Hz, 1H, H9β), 2.01 (d, J=1.1Hz, 3H, CH₃ 18), 2.22 (ddd, J=2.7, 10.7, 15.5 Hz, 1H, H6β), 2.45 (dd,J=4.8, 15.5 Hz, 1H, H6α), 2.54 (dd, J=9.1, 15.0 Hz, 1H, H14β), 2.86 (dd,J=3.7, 15.0 Hz, 1H, H14α), 3.07 (s, 1H, H3α), 3.40 (ddd, J=4.8, 4.8, 9.6Hz, 1H, H7α), 3.75 (s, 3H, CO₂Me ), 4.39 (dd, J=4.3, 11.2 Hz, 1H, H10β),4.60 (d, J=4.3, 11.2 Hz, 1H, H2β), 4.67 (dd, J=2.1, 9.1 Hz, 1H, H13β),12.24 (s, 1H, OH4).

[0269] Enol ester 17. To a stirred solution of crude enol ester 16(P₁₀=TES, P₁₃=TBS, R=Me) (1.02 g) in THF (13 mL) and 2-methoxypropene(13 mL) under nitrogen at 0° C. was added 0.48 mL of a 0.1 M solution(0.048 mmol) of p-toluenesulfonic acid in THF. The mixture was stirredat 0° C. for 10 min and then triethylamine (0.66 mL) was added. Themixture was concentrated under reduced pressure and purified by silicagel chromatography, eluting with 7.5% ethyl acetate in hexanesincreasing to 30% ethyl acetate in hexanes to yield 938 mg enol ester 17(P₇=MOP, P₁₀=TES, P₁₃=TBS, R=Me) (84% from 15) and 30 mg (3%) ofrecovered lactone ester 15.

[0270] 17 (P₇=MOP, P₁₀=TES, P₁₃=TBS, R=Me): mp 95-97° C., ¹H NMR (300MHz, CDCl₃) δ 0.08 (s, 3H, TBS CH₃), 0.10 (s, 3H, TBS CH₃), 0.59 (q,J=7.7 Hz, 6H, TES CH₃), 0.87 (s, 9H, TBS t-Bu), 0.95 (t, J=7.7 Hz, 9H,TES CH₃), 1.10 (s, 3H, CH₃), 1.19 (S, 3H, CH₃), 1.30 (s, 3H, CH₃), 1.34(s, 3H, MOP CH₃), 1.37 (s, 3H, MOP CH₃), 1.84 (m, 2H, H9α, H9β), 1.98(s, 3H, CH₃ 18), 2.17 (ddd, J=2.8, 10.4, 15.9 Hz, 1H, H6β), 2.52, (dd,J=9.3, 15.4 Hz, 1H, H14β), 2.63 (dd, J=4.4, 15.9 Hz, 1H, H6α), 2.88 (dd,J=3.8, 15.4 Hz, 1H, H14α), 3.06 (s, 1H, H3α), 3.26 (s, 3H, MOP OMe),3.37 (dd, J=4.4, 10.4 Hz, 1H, H7α) 3.72 (s, 3H, CO₂Me), 4.36 (dd, J=6.0,9.3 Hz, 1H, H10β), 4.57 (d, J=2.2 Hz, 1H, H2β), 4.67 (dd, J=2.8, 9.3 Hz,1H, H13β), 12.24 (s, 1H, OH4).

[0271] Enol ester 17 (P₇=TES). To a solution of the enol ester 16(P₁₀=TES, P₁₃=TBS, R=Me) (9 mg, 0.0137 mmole) and DMAP (3.5 mg, 0.0286mmole) in pyridine (0.6 mL) at 0° C. was added triethylsilyl chloride(0.025 mL, 0.14 mmole). The solution was stirred at room temperature for16 h, diluted with ethyl acetate (10 mL), poured into a saturatedaqueous sodium bicarbonate solution (20 mL) and extracted with 20% ethylacetate/hexane (20 mL ×3). The combined organic layer was dried overanhydrous NaSO₄, filtered and concentrated to yield 25 mg of crude 17.Column chromatography (10% ethyl acetate/hexane) provided 10 mg (95%) ofpure enol ester 17 (P₇=P₁₀=TES, P₁₃=TBS, R=Me).

[0272] 17 (P₇=P₁₀=TES, P₁₃=TBS, R=Me): ¹H NMR (300 MHz, CDCl₃) δ 0.08(s, 3H, TBS CH₃), 0.10 (s, 3H, TBS CH₃), 0.59 (q, J=8.1 Hz, 12H, TESCH₂,), 0.87 (s, 9H, TBS T-Bu), 0.95 (t, J=7.7 Hz, 18H, TES CH₃), 1.05(s, 3H, CH₃), 1.19 (s, 3H, CH₃), 1.30 (s, 3H, CH₃), 1.84 (m, 2H, H9α,H9β), 1.98 (s, 3H, CH₃ 18), 2.17 (ddd, J=2.8, 10.4, 15.9 Hz, 1H, H6β),2.31 (dd, J=4.4, 15.9 Hz, 1H, H6α), 2.52, (dd, J=9.3, 15.4 Hz, 1H,H14β), 2.85 )dd, J=3.8, 15.4 Hz, 1H, H14α), 3.03 (br s, 1H, H3α), 3.34(dd, J=5.0, 10.4 Hz, 1H, H7α), 3.75 (s, 3H, CO₂Me OMe), 4.36 (dd, J=5.0,10.4 Hz, 1H, H10β), 4.58 (d, J=2.7 Hz, 1H, H2β), 4.66 (br d, J=11.0 Hz,1H, H13β), 12.22 (s, 1H, OH4).

[0273] Ketone 18. To a stirred solution of enol ester 17 (P₇=MOP,P₁₀=TES, P₁₃=TBS, R=Me) (963 mg, 1.3 mmol) in DMF (30 mL) under nitrogenat room temperature was added solid potassium thiophenoxide (250 mg,1.69 mmol) followed by thiophenol (0.4 mL, 3.9 mmol). The solution waswarmed to 86° C. for 3.5 hours. The solution was allowed to cool to roomtemperature then was poured directly into 250 mL of a saturated aqueousNaHCO₃ solution and extracted with three 150 mL portions of 30% ethylacetate in hexanes. The combined organic phases were then filteredthrough a 2 inch silica gel pad and subsequently concentrated underreduced pressure to yield 1.29 g of crude product. This material waspurified by radial chromatography, eluting with 15% then 20% and finally25% ethyl acetate in hexanes to yield 763 mg (86%) of ketone 18 (P₇=MOP,P₁₀=TES, P₁₃=TBS).

[0274] 18 (P₇=MOP, P₁₀=TES, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ 0.10 (s,3H, TBS CH₃), 0.14 (s, 3H, TBS CH₃), 0.58 (q, J=8.2 Hz, 6H, TES CH₂),0.94 (s, 9H, TBS t-Bu), 0.95 (t, J=8.2 Hz, 9H, TES CH₃), 1.22 (s, 3H,CH₃ 19), 1.30 (s, 3H, CH₃ 17), 1.32 (s, 6H, MOP CH₃), 1.33 (s, 3H, CH₃16), 1.80 (m, 1H, H5), 1.81 (dd, J=3.8, 3.8 Hz, 1H, H9β), 1.98 (m, 1H,H5), 1.99 (d, J=1.1 Hz, 3H, CH₃ 18), 2.21 (m, 1H, H6β), 2.29 (dd,J=10.4, 12.1 Hz, 1H, H9α), 2.43 (dd, J=9.3, 15.4 Hz, 1H, H14α), 2.53 (m,1H, H6α), 2.63 (dd, J=5.0, 15.4 Hz, 1H, H14β), 2.70 (d, J=5.0 Hz, 1H,H3), 3.20 (s, 3H, MOP OMe), 3.39 (dd, J=6.1, 10.4 Hz, 1H, H7), 4.34 (dd,J=3.9, 10.4 Hz, 1H, H10), 4.55 (d, J=5.5 Hz, 1H, H2), 4.73 (dd, J=5.3,7.7 Hz, 1H, H13). Anal. Calcd. for C₃₆H₆₄O₈Si₂: C, 63.49; H, 9.47. FoundC, 63.56; H, 9.55.

[0275]18 (P₇=P₁₀=TES, P₁₃=TBS): 1H NMR (300 MHz, CDCl₃) δ 0.10 (s, 3H,TBS CH₃), 0.14 (s, 3H, TBS CH₃), 0.47-0.63 (m, 12H, TES CH₂), 0.90-0.99(m, 27H, TBS t-Bu, TES Ch₃), 1.22 (s, 3H, CH₃), 1.25 (s, 3H, CH₃), 1.33(s, 3H, CH₃), 1.75 (dt, J=11.6, 1.6 Hz, 1H), 1.85 (d, J=3.3 Hz, 1H),1.90 (t, J=3.9 Hz, 1H), 1.97 (t, J=8.1 Hz, 1H), 2.00 (s, 3H, CH₃), 2.30(m, 1H), 2.39-2.60 (m, 3H), 2.65 (m, 1H), 3.35 (dd, J=9.6, 7.8 Hz, 1H,H7α), 4.35 (dd, J=10.8, 3.3 Hz, 1H, H10β), 4.57 (d, J=5.1 Hz, 1H, H2β),4.72 (m, 1H, H13β),

[0276] Ketone 18 (P₇=BOM). To a stirred solution of ketone 18 (P₇=MOP,P₁₀=TES, P₁₃=TBS) (293 mg, 0.43 mmol) in THF (28.6 mL) and methanol (9.5mL) under nitrogen at room temperature was added dropwise 0.20 mL of a0.1 M solution of PPTS in CH₂Cl₂ (0.02 mmol). The reaction mixture wasstirred for 3 h, poured into 100 mL of a saturated aqueous NaHCO₃solution and extracted with two 100 mL portions of ethyl acetate. Thecombined organic phases were washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to yield 274 mg of thehydroxy ketone 18 (P₇=H) as a colorless oil. This material was usedwithout further purification.

[0277] 18 (P₇=H, P₁₀=TES, P₁₃=TBS): mp 75-77° C., ¹H NMR (500 MHz,CDCl₃) δ 0.10 (s, 3H, TBS CH₃), 0.13 (s, 3H, TBS CH₃), 0.61 (q, J=8.2Hz, 6H, TES CH₂), 0.93 (s, 9H, TBS t-Bu), 0.95 (t, J=7.7 Hz, 9H, TESCH₃), 1.19 (s, 3H, CH₃ 19), 1.22 (s, 3H, CH₃ 17), 1.35 (s, 3H, CH₃ 16),1.84 (dd, J=13.7, 4.1 Hz, 1H, H9α), 1.88 (m, 2H, H9β, OH7), 1.92 (m, 1H,H6β), 2.05 (d, J=1.4 Hz, 3H, CH₃ 18), 2.10 (m, 1H, H6α), 2.36 (dddd,J=1.4, 4.1, 9.9, 14.4 Hz, 1H, H5α), 2.47 (dd, J=8.9, 15.4 Hz, 1H, H14β),2.51 (m, 1H, H 5β), 2.54 (dd, J=4.8, 15.4 Hz, 1H, H14β), 2.86 (d, J=5.5Hz, 1H, H3), 3.59 (ddd, J=4.5, 6.2, 11.3 Hz, 1H, H7), 4.38 (dd, J=4.1,9.1 Hz, 1H, H10), 4.56 (d, J=5.5 Hz, 1H, H2), 4.69 (ddd, J=1.4, 4.8, 9.3Hz 1H, H13). Anal. Calcd. for C₃₂H₅₆O₇Si_(2×0.5)H₂O: C, 62.19; H, 9.30.Found C, 62.16; H, 9.22.

[0278] To a stirred solution of hydroxy ketone 18 (P₇=H) (179 mg, 0.29mmol) in CH₂Cl₂ (9.5 mL), diisopropylethylamine (1.49 mL, 8.6 mmol) andtetrabutylammonium iodide (253 mg, 0.69 mmol) under nitrogen was addeddropwise benzyloxymethylchloride (0.42 mL, 2.86 mmol). The reactionmixture was brought to reflux for 32 h, cooled to room temperature,poured into 100 mL of a saturated aqueous NaHCO₃ solution and extractedwith two 100 mL portions of 50% ethyl acetate in hexanes. The combinedorganic phases were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to yield 249 mg of the hydroxyketone as a yellowish oil. This material was purified by silica gelchromatography to yield 196 mg (92%) of ketone 18 (P₇=BOM, P₁₀=TES,P₁₃=TBS) as a colorless oil.

[0279] 18 (P₇=BOM, P₁₀=TES, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s,3H, TBS CH₃), 0.13 (s, 3H, TBS CH₃), 0.59 (q, J=7.7 Hz, 6H, TES CH₂),0.94 (s, 9H, TBS t-Bu), 0,94 (t, J=7.7 Hz, 9H, TES CH₃), 1.22 (s, 3H,CH₃ 17), 1.31 (s, 3H, CH₃ 19), 1.33 (s, 3H, CH₃ 16), 1.87 (dd, J=12.1,3.8 Hz, 1H, H9α), 1.98 (d, J=1.4 Hz, 3H, CH₃ 18), 1.99 (m, 2H, H6β,H9β), 2.21 (m, 1H, H660 ), 2.34 (dd, J=10.4, 12.1 Hz, 1H, H5α), 2.43(dd, J=9.3, 15.4 Hz, 1H, H14α), 2.55 (ddd, J=5.5, 11.0, 13.7 Hz, 1H,H5β), 2.62 (dd, J=5.0, 15.4 Hz, 1H, H14β), 2.74 (d, J=5.0 Hz, 1H, H3),3.38 (dd, J=6.6, 11 Hz, 1H, H7), 4.38 )dd, J=3.8, 10.4 Hz, 1H, H10),4.56 (d, J=5.0 Hz, 1H, H2), 4.58 (d, J=11.5 Hz 1H, CH₂Ph), 4.64 (d,J=11.5 Hz 1H, CH₂Ph), 4.68 (m, 2H, H13, OCH₂O), 4.82 (d, J=7.2 Hz 1H,OCH₂O), 7.31 (m, 5H, Ph).

[0280] Ketone 22a (P₅=TMS). To a vigorously stirred solution of ketone18 (P₇=BOM, P₁₀=TES, P₁₃=TBS) (315 mg, 0.42 mmol) in THF (10.5 mL),triethylamine (0.88 mL, 6.3 mmol) and trimethylsilyl chloride (0.53 mL,4.2 mmol) under nitrogen at −78° C. was added dropwise down the side ofthe flask 1.35 mL of a 0.5 M solution (0.68 mmol) of LDA in THF. After25 min, 2 mL of a saturated aqueous NaHCO₃ solution was added. Thereaction mixture was diluted with 150 mL of hexanes and washed with 20mL of a saturated aqueous NaHCO₃ solution and brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingoil was filtered through celite with hexanes and the filtrate wasconcentrated under reduced pressure to give 338 mg (99%) of the TMS enolether 21a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₄=TMS) as a colorless oil. To avigorously stirred solution of TMS enol ether 21a (P₇=BOM, P₁₀=TES,P₁₃=TBS, P₄=TMS) (224 mg, 0.274 mmol) in hexanes (2.8 mL) under nitrogenat room temperature was added dropwise 14.9 mL of a 0.02 M solution(0.30 mmol) of MCPBA in hexanes. After 5 h, 2 mL of a saturated aqueousNaHCO₃ solution and 2 mL of a 10% aqueous Na₂S₂O₃ solution were added.The reaction mixture was diluted with 150 mL of ethyl acetate and washedwith 20 mL of a saturated aqueous NaHCO₃ solution, 20 mL of a 10%aqueous Na₂S₂O₃ solution, 20 mL of a saturated aqueous NaHCO₃ solutionand brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give 231 mg of the crude material as a colorless oil. Thismaterial was used without further purification, or, alternatively, waspurified by flash chromatography on silica gel to give 168 mg (74%) of22a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS) along with a mixture (15%) of 21aand 18 which could be recycled.

[0281] 22a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS): mp 50.5-52° C., ¹H, NMR(500 MHz, CDCl₃) δ 0.10 (s, 3H, TBS CH₃), 0.13 (s, 9H, TMS CH₃), 0.14(s, 3H, TBS CH₃), 0.59 (a, J=8.2 Hz, 6H, TES CH₂), 0.94 (s, 9H, TBSt-Bu), 0.94 (t, J=8.2 Hz, 9H, TES CH₃), 1.24 (s, 3H, CH₃ 17), 1.32 (s,3H, CH₃ 19), 1.33 (s, 3H, CH₃ 16), 1.82 (dd, J=11.3, 13.7 Hz, 1H, H9α),1.95 (d, J=1.4 Hz, 3H, CH₃ 18), 1.98 (dd, J=3.4, 13.7 Hz, 1H, H9,β),2.16 (ddd, J=6.2, 7.2, 13.3 Hz, 1H, H6α), 2.40 (dt, J=11.4, 13.3 Hz,6β), 2.43 (dd, J=9.2, 15.2 Hz, 1H, H14β), 2.63 (dd, J=5.5, 15.2 Hz, 1H,H14α), 2.74 (d, J=5.5 Hz, 1H, H3α), 3.40 (dd, J=7.2, 10.6 Hz, 1H,H7α),4.36 (dd, J=3.4, 11.3 Hz, 1H, H10β), 4.40 (dd, J=6.2, 12.0 Hz, 1H,H5α), 4.54 (d, J=5,5 Hz, 1H, H2β), 4.57 (d, J=11.7 Hz 1H, CH₂Ph), 4.64(d, J=11.7 Hz 1H, CH₂Ph), 4.68 (d, J=7.0 Hz 1H, OCH₂O), 4.74 (m, 1H,H13), 4.78 (d, J=7.0 Hz, 1H, OCH₂O), 7.31 (m, 5H, Ph). Anal. Calcd. forC₄₃H₇₂O₉Si₃: C, 63.19; H, 8.88. Found C, 63.19; H, 8.92.

[0282] Ketone 22a (P₅=H). To a vigorously stirred solution of crude 22a(P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS) (231 mg, 0.274 mmol) in acetonitrile(7 mL) at 0° C. was added dropwise 7 mL of a 1:10:10 (by volume) mixtureof 48% aqueous HF:pyridine:acetonitrile . After stirring for 20 min, 2mL of a saturated aqueous NaHCO₃ solution was added. The reactionmixture was diluted with 150 mL of ethyl acetate and washed with 30 mLof a saturated aqueous NaHCO₃ solution and brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to give 223 mg of thecrude alcohol as a colorless oil. This material was purified by silicagel chromatography to yield 155 mg (74%) of ketone 22a (P₇=BOM, P₁₀=TES,P₁₃=TBS, P₅=H), 15 mg (7%) of the 5β-hydroxy ketone and 33 mg (14%recoverable material) of a 1:1 mixture of TMS enol ether 21a and ketone18.

[0283]22a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=H): ¹H NMR (500 MHz, CDCl₃) δ0.10 (s, 3H, TBS CH₃), 0.14 (s, 3H, TBS CH₃), 0.59 (q, J=8.2 Hz, 6H, TESCH₂), 0.94 (s, 9H, TBS t-Bu), 0.94 (t, J=8.2 Hz, 9H, TES CH₃), 1.23 (s,3H, CH₃ 19), 1.32 (s, 3H, CH₃ 17), 1.33 (s, 3H, CH₃ 16), 1.83 (dd,J=11.0, 13.7 Hz, 1H, H6β), 1.97 (d, J=1.4 Hz, 3H, H18), 2.01 (dd, J=3.2,13.7 Hz, 1H, H9β), 2.11 (ddd, J=5.5, 7.7, 13.7 Hz, 1H, H6α), 2.47 (dd,J=8.7, 15.4 Hz, 1H, H14β), 2.57 (m, 2H, H14α, H9α), 2.88 (d, J=5.5 Hz,1H, H3α), 3.39 (dd, J=7.7, 11.0 Hz, 1H, H7α), 3.41 (d, J=3.3 Hz, 1H,OH−5), 4.38 (m, 2H, H5β, H10), 4.55 (d, J=5.5 Hz, 1H, H2β), 4.57 (d,J=11.5 Hz 1H, CH₂Ph), 4.62 (d, J=111.5 Hz 1, CH₂Ph), 4.72 (m, 2H, H13β,OCH₂O ), 4.80 (d, J=7.1 Hz 1H, OCH₂O ), 7.31 (m, 5H, Ph).

[0284] Ketone 22a (P₅=TMS) from ketone 22a (P₅=H). To a vigorouslystirred solution of 5-hydroxy-4-ketone 22a (P₇=BOM, P₁₀=TES, P₁₃=TBS,P₅=H) (51 mg, 0.067 mmol) in CH₂Cl₂ (2.2 mL) and triethylamine (0.14 mL,1.0 mmol) under nitrogen at 0° C. was added trimethylsilylchloride(0.041 mL, 0.34 mmol). After 0.5 h, the reaction mixture was quenchedwith 5 mL of a saturated aqueous NaHCO₃ solution and extracted with 150mL hexanes. The organic phase was washed with 50 mL of a saturatedaqueous NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give 56 mg a colorless oil. Thismaterial was filtered through silica gel and the filtrate wasconcentrated under reduced pressure to yield 54 mg (96 %) of ketone 22a(P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS).

[0285] Alcohol 23a. To a stirred solution of ketone 22a (P₇=BOM,P₁₀=TES, P₁₃=TBS, P₅=TMS) (18.9 mg, 0.023 mmol) in CH₂Cl₂ (4 mL) undernitrogen at −65° C. was added dropwise a 0.073 mL of a 3.1 M solution ofMeMgBr in ether (0.23 mmol). The reaction mixture was allowed to warm to−48° C., stirred for 16.5 h and then quenched with 0.13 mL of a 2.0Msolution of AcOH in THF (0.25 mmol) and then poured into a stirringmixture of 50 mL of a saturated aqueous NaHCO₃ solution and 50 mL ofethyl acetate. The aqueous phase was extracted with 50 mL ethyl acetate.The combined organic phases were washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to yield 20.5 mg of acolorless oil. This material was purified by silica gel chromatographyto yield 18.4 mg (95%) of alcohol 23a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS)as a colorless oil.

[0286] 23a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS): ¹H NMR (500 MHz, CDCl₃) δ0.09 (s, 9H, TMS), 0.11 (s, 3H, TBS CH₃), 0.12 (s, 3H, TBS CH₃), 0.56(q, J=7.9 Hz, 6H, TES CH₂), 0.92 (t, J=7.9 Hz, 9H, TES CH₃), 0.93 (s,9H, TBS t-Bu), 1.25 (s, 3H, CH₃ 17), 1.28 (s, 3H, CH₃ 19), 1.33 (s, 3H,CH₃ 20), 1.34 (s, 3H, CH₃ 16), 1.74 (ddd, J=3.8, 4.1, 13.0 Hz, 1H, H6α),1.99 (d, J=1.4 Hz, 3H, H18), 2.01 (dd, J=11.3, 13.0 Hz, 1H, H9α), 2.06(m, 2H, H3, H9β), 2.13 (ddd, J=1.7, 12.3, 13.0 Hz, 1H, H6β), 2.37 (dd,J=5.5, 15.0 Hz, 1H, H14α), 2.54 (dd, J=9.2, 15.0 Hz, 1H, H14β), 2.96 (s,1H, OH−4), 3.51 (dd, J=1.7, 4.1 Hz, 1H, H5), 3.73 (dd, J=3.8, 12.3 Hz,1H, H7α), 4.32 (dd, J=4.1, 11.3 Hz, 1H, H10β), 4.64 (s, 2H, CH₂Ph), 4.72(d, J=6.8 Hz, 1H, OCH₂O), 4.80 (m, 3H, H2, H13, OCH₂O), 7.31 (m, 5H,Ph). Anal. Calcd. for C₄₄H₇₆O₉Si₃: C, 63.42; H, 9.19. Found C, 63.40; H,9.15.

[0287] Hydroxy olefin 24a. To a refluxing solution of alcohol 23a(P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS) (46.7 mg, 0.055 mmol) in toluene (1.1mL) was added 1.1 mL of a 0.1M solution of Burgess reagent in toluene (0.11 mmol). The mixture was refluxed for 20 min then cooled to roomtemperature, diluted with ethyl acetate, washed with a saturatedsolution of NaHCO₃ and brine, dried over anhydrous Na₂SO₄ and filtered.Concentration of the filtrate under vacuum yielded 46 mg of crudeolefin. This material was used without further purification.

[0288] To a stirred solution of this crude olefin (46 mg, 0.055 mmol) inacetonitrile (2.5 mL) at 0° C. was added 2.5 mL of a 1:10:10 (by volume)mixture of 48% aqueous HF: pyridine: acetonitrile. The mixture wasstirred at 0° C. for 20 min, quenched with a saturated solution ofNaHCO₃ and extracted twice with ethyl acetate. The combined organicphases were washed with brine, dried over anhydrous Na₂SO₄ and filtered.Concentration of the filtrate under vacuum yielded 48 mg of a colorlessoil which was purified by silica gel chromatography to yield 25.9 mg(62%) of hydroxy olefin 24a (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=H) as well as2.1 mg of unreacted alcohol 23a (4%).

[0289] 24a (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=H): mp 66-68° C. ¹H NMR (500MHz, CDCl₃) δ 0.12 (s, 3H, TBS CH₃), 0.13 (s, 3H, TBS CH₃), 0.59 (q,J=7.9 Hz, 6H, TES CH₂), 0.94 (t, J=7.9 Hz, 9H, TES CH₃), 0.95 (s, 9H,TBS t-Bu), 1.18 (s, 3H, CH₃ 19), 1.23 (s, 3H, CH₃ 17), 1.35 (s, 3H, CH₃16), 1.73 (d, 1H, J=3.4 Hz, OH5), 1.83 (dd, J=9.9, 10.5 Hz, 1H, H9α),1.91 (ddd, J=7.2, 7.5, 13.4 Hz, 1H, H6α), 1.97 (dd, J=3.8, 9.9 Hz, 1H,H9β), 2.03 (d, J=1.4 Hz, 3H, 18), 2.14 (ddd, J=9.6, 9.6, 13.4 Hz, 1H,H6β) 2.35 (dd, J=5.1, 15.4 Hz, 1H, H14α), 2.50 (dd, J=9.6, 15.4 Hz, 1H,H14β), 3.03 (d, J=5.8 Hz, 1H, H3α), 3.44 (dd, J=7.5, 9.6, Hz, 1H, H7α),4.38 (m, 2H, H10, H5), 4.54 (d, J=5.8 Hz, 1H, H2), 4.58 (d, J=11.6 Hz,1H, CH₂Ph), 4.62 (d, J=11.6 Hz, 1H, CH₂Ph), 4.73 (d, J=7.0 Hz, 1H,OCH₂O), 4.75 (m, 1H, H13), 4.79 (d, J=7.0 Hz, 1H, OCH₂O), 5.00 (s, 1H,H20E), 5.18 (s, 1H, H20Z), 7.31 (m, 5H, Ph). Anal. Calcd. forC₄₁H₆₆O₈Si₂×0.5H₂O: C, 65.47; H, 8.98. Found C, 65.63; H, 8.97.

[0290] Allyl mesylate 24aa. To a stirred solution of allyl alcohol 24a(P₇=BOM, P₁₀=TES, P₁₃=TBS, R=H) (11.5 mg, 0.0154 mmol) in pyridine (0.6mL) under nitrogen at 0° C. was added dropwise methanesulfonyl chloride(0.02 mL, 0.258 mmol). After 45 min, a saturated aqueous NaHCO₃ solution(0.05 mL) was added. The mixture was stirred for 10 min, poured into 20mL of a saturated aqueous NaHCO₃ solution and extracted with 40% ethylacetate/hexane (20 mL ×3). The combined organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give 13 mgof 24aa (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ms) as a colorless oil. Thismaterial was used without further purification.

[0291] 24aa (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ms): ¹H NMR (300 MHz, CDCl₃); δ0.12 (s, 3H, TBS CH₃), δ 0.13 (s, 3H, TBS CH₃), 0.58 (q, J=7.9 Hz, 6H,TES CH₂), 0.93 (s, 9H, TBS t-Bu), 0.94 (t, J=7.9 Hz, 9H, TES CH₃), 1.23( s, 3H, CH₃ 17), 1.22 (s, 3H, CH₃ 19), 1.34 (s, 3H, CH₃ 16), 1.80 (brt, J=13 Hz, 1H, H9α), 1.98 (m, 1H, H6), 1.79 (ddd, J=2.2, 5.5, 15.1 Hz,1H, H14α), 2.01 (d, J=1.1 Hz, 1H, CH₃18), 2.06 (dd, J=3.3, 13.7 Hz, 1H,H9β), 2.01 (br s, 3H, CH3 18), 2.22-2.32 (m, 3H, H14α, H6α, H6β), 2.54(dd, J=9.9, 15.4 Hz, 1H, H14β), 3.02 (s, 3H, OSO₂CH₃), 3.05 (d, J=6.0Hz, 1H, H3α), 3.45 (t, J=8.5 Hz, 1H, H7α), 4.37 (dd, J=3.6, 11.0 Hz, 1H,H10β), 4.57 (d, J=6.0 Hz, 1H, H2β), 4.59 (q, 2H, PhCH₂O), 4.69 (d, J=7.1Hz, 1H, OCH₂O), 4.74 (m, 1H, H13β), 4.76 (d, J=7.1 Hz, 1H, OCH₂O), 5.03(br t, J=8.5 Hz, 1H, H5β), 5.09 (br s, 1H, H20), 5.24 (br, s 1H, H20),7.35 (m, 5H, Ph).

[0292] Triol 25a. To a stirred solution of allyl alcohol 24a (P₇=BOM,P₁₀=TES, P₁₃=TBS, R=H) (45 mg, 0.0606 mmol) in a mixture of pyridine(0.32 mL) and ether (3.2 mL) under nitrogen at 0° C. was added a 0.157 Msolution of OsO₄ in THF (0.42 mL, 0.066 mmole). After 12 h at 0° C.,NaHSO₃ (530 mg), pyridine (0.3 mL), THF (2 mL) and water (3 mL) wereadded. The mixture was vigorously stirred at room temperature for 14 h,poured into 50 mL of a saturated aqueous NaHCO₃ solution and extractedwith ethyl acetate (40 mL ×3). The combined organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give 60 mgof a pale yellow oil, which was column chromatographed (30% ethylacetate/hexane) to yield 34.3 mg (73%) of triol 25a (P₇=BOM, P₁₀=TES,P₁₃=TBS).

[0293] 25a (P₇=BOM, P₁₀=TES, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃); δ 0.11(s, 6H, TBS CH₃), 0.60 (ddd, J=9.0 Hz, 6H, TES CH₂), 0.79 (s, 3H, CH₃19), 0.93 (s, 9H, TBS t-Bu), 0.94 (dd, J=9.0 Hz, 9H, TES CH₃), 1.22 (s,3H, CH₃ 17), 1.35 (s, 3H, CH₃ 16), 1.64 (dd, J=5.6, 16.4 Hz, 1H, H9β),1.70 (m, 1H, H6β), 2.22 (dd, J=2.7, 16.8 Hz, 1H, H9α), 2.23 (d, J=0.7Hz, 3H, CH₃ 18),, 2.36 (dd, J=9.2, 15.0 Hz, 1H, H14β), 2.45 (m, 1H,H6α), 2.96 (s, 1H, OH5), 3.21 (dd, 6.9, 15.0 Hz, 1H, H14α), 3.42 (d,J=5.0 Hz, 1H, H3α), 3.53 (m, 1H, H20), 3.38 (s, 1H, OH4), 3.70 (t, J=3.0Hz, 1H, H5β), 4.04 (br D, J=11 Hz, 1H, H20), 4.06 (dd, J=11.5, 5.0 Hz,1H, H7α), 4.48 (d, J=5.0 Hz, 1H, H2β), 4.49 (d, J=12.0 Hz, 1H, PhCH₂O),4.53 (br s, 1H, H10β), 4.71 (m, 1H, H13β), 4.72 (d, J=12.0 Hz, 1H,PhCH₂O), 4.85 (d, J=6.8 Hz, 1H, OCH₂O), 4.98 (d, J=6.8 Hz, 1H, OCH₂O),7.34 (m, 5H, Ph). Anal. Calcd. for C₄₁H₆₈O₁₀Si₂: C, 63.36; H, 8.82.Found C, 63.19; H, 8.75.

[0294] Diol mesylate 26a. To a stirred solution of allyl mesylate 24aa(P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ms) (5 mg, 0.0064 mmol) in a mixture ofpyridine (0.4 mL) and THF (0.4 mL) under nitrogen at room temperaturewas added a 0.157 M solution of OSO₄ in THF (0.06 mL). After 7 h, NaHSO₃(150 mg) and water (0.2 mL) were added. The mixture was vigorouslystirred for 14 h, poured into 20 mL of a saturated aqueous NaHCO₃solution and extracted with ethyl acetate (20 mL ×3). The combinedorganic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give 6 mg of a pale yellow oil. The oil was columnchromatographed (40% ethyl acetate/hexane) to yield 2.7 mg (50%) of diolmesylate 26a (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ms).

[0295] 26a (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ms): ¹H NMR (500 MHz, CDCl₃); δ0.14 (s, 6H, TBS CH₃), 0.58 (ddd, J=8.0 Hz, 6H, TES CH₂), 0.89 (s, 3H,CH₃ 19), 0.93 (s, 9H, TBS t-Bu), 0.94 (dd, J=8.0 Hz, 9H, TES CH₃), 1.31(s, 3H, CH₃ 17), 1.37 (s, 3H, CH₃ 16), 1.76 (dd, J=5.5, 15.1, 1Hz, H9β),1.95 (m, 1H, H6β), 2.23 (d, J=0.7 Hz, 3H, CH₃ 18), 2.25 (dd, J=4.8, 15.1Hz, 1H, H9α), 2.39 (dd, J=9.2, 15.1 Hz, 1H, H 14β), 2.45 (m, 1H, H6α),2.89 (dd, 6.8, 15.1 Hz, 1H, H14α), 3.05 (d, J=3.4 Hz, 1H, H3α), 3.06 (s,3H, OSO₂CH₃), 3.35 (s, 1H, OH4), 3.52 (m, 1H, H20), 3.92 (dd, J=4.5,11.6 Hz, 1H, H7α), 4.13 (dd, J=1.0, 11.3 Hz, 1H, H20), 4.46 (br d, J=4.5Hz, 1H, H10), 4.52 (d, J=3.4 Hz, 1H, H2), 4.54 (d, J=12.0 Hz, 1H,PhCH₂O), 4.70 (d, J=12.0 Hz, 1H, PhCH₂O), 4.83 (d, J=6.9 Hz, 1H, OCH₂O),4.84 (m, 1H, H5β), 4.92 (m, 1H, H13β), 4.93 (d, J=6.9 Hz, 1H, OCH₂O),7.34 (m, 5H, Ph).

[0296] Diol tosylate 26aa. To a stirred solution of triol 25a (P₇=BOM,P₁₀=TES, P₁₃=TBS) (37 mg, 0.0476 mmole) in CH₂Cl₂ (0.4 mL) undernitrogen at −78° C. was added triethylamine (0.25 mL) followed bytrimethylchlorosilane (0.075 mL). The solution was stirred at −78° C.for 1 h, poured into 20 mL of a saturated aqueous NaHCO₃ solution andextracted with chloroform (30 mL ×3). The combined organic phase wasdried over anhydrous Na₂SO_(4,) and concentrated under reduced pressureto give 38.2 mg of a colorless oil. This oil was dissolved in THF (0.5mL) and cooled to −78° C. To this solution was added a 0.2 M solution ofLDA in THF (0.9 mL, 0.18 mmole). After 20 min at −78° C.,p-toluenesulfonyl chloride (35 mg, 0.183 mmole) was added. Afterstirring at −35° C. for 3 h, MeOH (0.2 mL) and diethylamine (0.3 mL)were added. The solution was stirred at −35° C. for 30 min and pouredinto 30 mL of a saturated aqueous NaHCO₃ solution and extracted withchloroform (40 mL ×3). The combined organic phases were dried overanhydrous Na₂SO₄, and concentrated under reduced pressure to give 58 mgof a colorless oil. The oil was dissolved in acetonitrile (3.6 mL) andpyridine (3.6 mL). To this solution at 0° C. was added 48% aqueoussolution of HF (0.36 mL). The solution was stirred at 0° C. for 15 min,poured into 30 mL of a saturated aqueous NaHCO₃ solution and extractedwith chloroformn (40 mL ×3). The combined organic phase was dried overanhydrous Na₂SO₄, and concentrated under reduced pressure to give 56 mgof crude diol tosylate 26aa. Column chromatography (40%ethylacetate/hexane) yielded 34 mg (80 %) diol tosylate 26aa (P₇=BOM,P₁₀=TES, P₁₃=TBS, R=Ts).

[0297] 26aa (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ts). ¹H NMR (300 MHz, CDCl₃); δ0.18 (s, 6H, TBS CH₃), 0.58 (d, J=12.5 Hz, 6H, TES CH₂), 0.82 (s, 3H,CH₃ 19), 0.94 (dd, J=13.0 Hz, 9H, TES CH₃), 0.97 (s, 9H, TBS t-Bu), 1.28(s, 3H, CH₃ 17), 1.34 (s, 3H, CH₃ 16), 1.67 (dd, J=16.5, 4.4 Hz, 1H,H9β), 1.80 (m, 1H, H6β), 2.13 (dd, J=16.5, 4.4 Hz, 1H, H9α), 2.18 (m,1H, H6α), 2.24 (s, 3H, CH₃ 18), 2.33 (s, 3H, CH₃Ph), 2.42 (dd, J=14.8,9.3 Hz, 1H, H14β), 2.90 (m, 1H, H14α), 2.93 (br s, 1H, OH4), 3.08 (br d,J=3.3 Hz, 1H, H3α), 3.38 (br t, J=11.0 Hz, 1H, H7α), 3.87 (m, 1H, H20),4.09 (br d, J=9.9 Hz, 1H, H20), 4.52 (d, J=3.3 Hz, 1H, H2β), 4.45 (br d,J=4.4 Hz, 1H, H10β), 4.46 (d, J=12.1 Hz, 1H, PhCH₂O), 4.59 (d, J=12.1Hz, 1H, PhCH₂O), 4.66 (br t, J=3.8 Hz, 1H, H5β), 4.75 (d, J=7.1 Hz, 1H,OCH₂O), 4.83 (d, J=7.1 Hz, 1H, OCH₂O), 4.89 (br dd, J=7.7, 6.6 Hz, 1H,H13β), 7.14 (d, J=8.2 Hz, 2H, SO₂Ph), 7.34 (m, 5H, OCH₂Ph), 7.75 (d,J=8.2 Hz, 2H, SO₂Ph).

[0298] Oxetane 27a from diol mesylate 26a. To a stirred solution of diolmesylate 26a (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ms) (2.7 mg) in toluene (0.4mL) under nitrogen at room temperature was added diisopropyl ethylamine(0.008 mL). The solution was refluxed for 3.5 h, cooled to roomtemperature, poured into 20 mL of a saturated aqueous NaHCO₃ solutionand extracted with ethyl acetate (20 mL ×3). The combined organic phasewas dried over anhydrous Na₂SO₄, and concentrated under reduced pressureto give 3 mg of a pale yellow oil. The oil was column chromatographed(30% ethyl acetate/hexane) to yield 1 mg (42%) of oxetane 27a.

[0299] 27a (P₇=BOM, P₁₀=TES, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃); δ 0.10(s, 6H, TBS CH₃), 0.59 (dd, J=8.0 Hz, 6H, TES CH₂), 0.92 (s, 9H, TBSt-Bu), 0.94 (dd, J=8.0 Hz, 9H, TES CH₃), 1.20 ( s, 3H, CH₃ 17), 1.26 (s,3H, CH₃ 19), 1.32 (s, 3H, CH₃ 16), 1.93 (dd, J=11.3, 13.4 Hz, 1H, H9α),1.98 (d, J=1.4 Hz, 3H, CH₃ 18), 2.06 (dd, J=6.0, 18.6 Hz, 1H, H6β), 2.11(dd, J=4.5, 13.4 Hz, 1H, H9β), 2.14 (d, J=5.5 Hz, 1H, H3α), 2.41 (dd,J=9.2, 15.1 Hz, 1H, H14β), 2.43 (m, 1H, H6α), 2.54 (s, 1H, OH4), 2.76(dd, J=5.2, 15.1 Hz, H14α), 3.21 (dd, J=3.4, 13.0 Hz, 1H, H7α), 4.36 (d,J=8.6 Hz, 1H, H20α), 4.37 (dd, J=4.1, 11.3 Hz, 1H, H10β), 4.40 (br d,J=8.2 Hz, 1H, H5α), 4.60 (d, J=5.5 Hz, 1H, H2β), 4.61 (d, J=12.6 Hz, 1H,PhCH₂O), 4.67 (m, 1H, H13β), 4.69 (d, J=12.6 Hz, 1H, PhCH₂O), 4.75 (d,J=7.5 Hz, 1H, OCH₂O), 4.86 (d, J=7.5 Hz, 1H, OCH₂O), 4.91 (dd, J=0.7,8.6 Hz, 1H, H20β), 7.34 (m, 5H, Ph). Anal. Calcd. for C₄₁H₆₆O₉Si₂: C,64.87; H, 8.76. Found C, 64.61; H, 8.78.

[0300] Oxetane 27a from diol tosylate 26aa. To a stirred solution ofdiol tosylate 26aa (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ts) (33 mg, 0.0354mmole) in toluene (3.3 mL) under nitrogen at room temperature was addedDBU (0.11 mL, 0.73 mmole). The solution was heated at 80° C. for 10 min,then the temperature was increased up to 110° C. during a 40 min period,maintained at 110° C. for 30 more min and cooled to room temperature.Thesolution was filtered through a short pad of silica gel using 30% ethylacetate/hexane as eluent. The filtrate was concentrated to give 25 mg ofcrude 27a, which was column chromatographed (30% ethyl acetate/hexane)to yield 21 mg (78%) of oxetane 27a (P₇=BOM, P₁₀=TES, P₁₃=TBS).

[0301] Oxetane 29. To a stirred solution of oxetane 27a (P₇=BOM,P₁₀=TES, P₁₃=TBS) (21 mg, 0.0276 mmloe) and dimethylaminopyridine (3.4mg, 0.0278 mmole) in pyridine (110 μL, 1.37 mmole) under nitrogen atroom temperature was added acetic anhydride (26 μL, 0.276 mmole). Thesolution was stirred for 25 h, diluted with ethyl acetate, poured into20 mL of saturated aqueous NaHCO₃ solution and extracted with ethylacetate (20 mL ×3). The combined organic phases were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give 26 mgof a pale yellow oil, which was column chromatographed (25% ethylacetatelhexane) to yield 16 mg (72%) of oxetane 29 (P₇=BOM, P₁₀=TES,P₁₃=TBS).

[0302] 29 (P₇=BOM, P₁₀=TES, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃); δ 0.10(s, 3H, TBS CH₃), 0.12 (s, 3H, TBS CH₃), 0.56 (q, 6H, TES CH₂), 0.92 (t,9H, TES CH₃), 0.94 (s, 9H, TBS t-Bu), 1.35 (s, 3H, CH₃ 16), 1.30 (s, 3H,CH₃ 17), 1.29 (s, 3H, CH₃ 19), 1.96 (br t, J=13.0 Hz, 1H, H9α), 1.98 (d,J=1.4 Hz, 3H, CH₃ 18), 2.02 (dd, J=7.5, 13.0, 1H, H9β), 2.07 (dt, J=8.0,13.0 Hz, 1H, H6β), 2.13(s, 3H, OAc), 2.24 (dd, J=3.4, 15.0 Hz, 1H,H14α), 2.40 (dd, J=8.6, 15.0 Hz, 1H, H14β), 2.51 (ddd, J=4.1, 9.2, 15.0Hz, 1H, H6α), 2.63 (d, J=6.5 Hz, 1H, H3α), 3.69 (dd, J=4.1, 13.0 Hz,H7α), 4.35 (dd, J=3.4, 11.3 Hz, 1H, H10β), 4.64 (m, 4H, PhCH₂O, H2β,H5α), 4.75 (d, J=7.2 Hz, 1H, OCH₂O), 4.76 (br d, J=9.2 Hz, 1H, H20),4.83 (d, J=7.2 Hz, 1H, OCH₂O), 4.85 (br d, J=9.2 Hz, 1H, H20), 4.88 (brt, J=8.2 Hz, 1H, H13β), 7.35 (m, 5H, Ph).

[0303] Benzoate 30. To a stirred solution of oxetane 29 (P₇=BOM,P₁₀=TES, P₁₃=TBS) (6 mg, 0.0075 mmol) in THF (0.5 mL) under nitrogen at−78° C. was added a 0.3M solution of phenyllithium in ether (44 μL,0.013 mmol). The solution was stirred at −78° C. for 15 min and quenchedwith a 10% solution of acetic acid in THF. The solution was diluted withethyl acetate, poured into 20 mL of a saturated aqueous NaHCO₃ solutionand extracted with ethyl acetate (20 mL ×3). The combined organic phaseswere dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto give 8 mg of a pale yellow oil. The oil was column chromatographed(25% ethyl acetate/hexane) to yield 6.2 mg (94%) of benzoate 30 (P₇=BOM,P₁₃=TBS, R=TES).

[0304] 30 (P₇=BOM, P₁₃=TBS, R=TES): ¹H NMR (500 MHz, CDCl₃); δ 0.09 (s,3H, TBS CH₃), 0.14 (s, 3H, TBS CH₃), 0.60 (ddd, 6H, TES CH₂), 0.94 (s,9H, TBS t-Bu), 0.96 (t, 6H, TES CH₃), 1.23 ( s, 3H, CH₃ 17), 1.38 (s,3H, CH₃ 19), 1.46 (s, 3H, CH₃ 16), 1.69 (s, 1H, OH1), 1.97 (ddd, J=14.5,10.0, 3.1 Hz, 1H, H6β), 2.05 (dd, J=16.1, 5.1 Hz, 1H, H9β), 2.09 (dd,J=15.1, 6.2 Hz, 1H, H14β), 2.13 (s, 3H, CH₃ 18), 2.22 (dd, J=15.1, 8.2Hz, 1H, H14α), 2.23 (dd, J=15.0, 8.5 Hz, 1H, H9β), 2.24 (s, 1H, OAc 4),2.38 (dd, J=16.1, 4.1 Hz, 1H, H9α), 2.67 (m, 1H, H6α), 3.40 (d, J=6.2Hz, 1H, H3α), 3.99 (dd, J=10.1, 6.8 Hz, 1H, H7α), 4.20 (d, J=8.2 Hz, 1H,H20β), 4.29 (d, J=8.2 Hz, 1H, H20α), 4.49 (d,J=12.0 Hz, 1H, PhCH₂O),4.63 (br t, 1H, H10β), 4.74 (d,J=12.0 Hz, 1H, PhCH₂O), 4.92 (d, J=6.9Hz, 1H, OCH₂O), 4.91-4.95 (m, 2H, H13βH5α), 5.01(d, J=6.9 Hz, 1H,OCH₂O), 5.66 (d, J=6.2 Hz, 1H, H2β), 7.28 (m, 1H, PhCH₂), 7.35 (m, 4H,PhCH₂), 7.48 (m, 2H, PhCOO-m), 7.59 (m, 1H, PhCOO-p), 8.11 (m, 2H,PhCOO-o).

[0305] Alcohol 31. To a solution of benzoate 30 (P₇=BOM, P₁₃=TBS, R=TES)(6.2 mg, 0.007 mmol) in 2 mL of THE was added 0.1 mL of a 0.1 M solutionof TBAF in THEF. The mixture was stirred for 2 h at 25° C. undernitrogen. The reaction mixture was diluted with 10 mL of ethyl acetate,then poured into 10 mL of a saturated aqueous NaHCO₃ solution. Theorganic phase was washed with 10 mL of a saturated aqueous NaHCO₃solution, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give 4.5 mg (93%) of alcohol 31 (P₇=BOM, P₁₃=TBS, R=H).

[0306] 31 (P₇=BOM, P₁₃=TBS, R=H): mp 213-216° C. ¹H NMR (500 MHz,CDCl₃); δ 0.10 (s, 3H, TBS CH₃), 0.15 (s, 3H, TBS CH₃), 0.94 (s, 9H, TBSt-Bu), 1.26 ( s, 3H, CH₃ 17), 1.39 (s, 3H, CH₃ 19), 1.45 (s, 3H, CH₃16), 1.68 (s, 1H, OH1), 1.89 (ddd, J=14.5, 10.0, 2.5 Hz, 1H, H6β), 2.10(dd, J=15.0,9.0 Hz, 1H, H14β), 2.15 (dd, J=15.0, 8.0 Hz, 1H, H14α), 2.18(s, 3H, CH₃ 18), 2.23 (dd, J=15.0, 8.5 Hz, 1H, H9β), 2.26 (s, 1H, OAc4), 2.40 (dd, J=15.0, 3.5 Hz, 1H, H9α), 2.68 (m, 1H, H6α), 2.90 (br s,1H, OH10), 3.54 (d, J=6.0 Hz, 1H, H3α), 4.16 (d, J=8.0 Hz, 1H, H20β),4.23 (dd, J=10.0, 7.0 Hz, 1H, H7α), 4.30 (d, J=8.0 Hz, 1H, H20α), 4.68(dd,J=15 Hz, 2H, PhCH₂O), 4.78 (m, 1H, H10β), 4.87 (d, J=6.5 Hz, 1H,OCH₂O), 4.95 (t, J=2.0 Hz, 1H, H20α), 4.92 (d, J=7.0 Hz, 1H, OCH₂O),4.93 (br d, J=2.0 Hz, 1H, H13β), 4.96 (br d, J=6.5 Hz, 1H, H5α), 4.97(d, J=6.5 Hz, 1H, OCH₂O), 5.68 (d, J=6.0 Hz, 1H, H2β), 7.28 (m, 1H,PhCH₂O), 7.35 (m, 4H, PhCH₂O), 7.40 (m, 2H, PhCOO-m), 7.59 (m, 1H,PhCOO-p), 8.13 (m, 2H, PhCOO-o). Anal. Calcd. for C₄₃H₆₀O₁₀Six0.5H₂O: C,66.72; H, 7.94. Found C, 66.75; H, 7.96.

[0307] Alcohol 31 through Alcohol 30a. To a stirred solution of oxetane29 (P₇=BOM, P₁₀=TES, P₁₃=TBS) (16 mg, 0.02 mmole) in acetonitrile (0.33mL) at 0° C. was added a 4% solution of HF-pyridine complex inacetonitrile (0.8 mL). The solution was stirred at 0° C. for 11 h,diluted with ethyl acetate, poured into 20 mL of a saturated aqueousNaHCO₃ solution and extracted with CHCl₃ (30 mL ×3). The combinedorganic phases were dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give 13.5 mg (0.0196 mmole) of 30a as an oil. Thisoil was dissolved in THF (1 mL) and cooled to −78° C. To this solutionat −78° C. was added a 0.285 M solution of phenyllithium in THF (0.144mL, 2.1 eq.). After 10 min, the solution was poured into 20 mL ofsaturated aqueous NaHCO₃ solution and CHCl₃ (30 mL ×3). The combinedorganic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give 16 mg of a pale yellow oil, which wascrystalized to yield 12.7 mg (85%) of benzoate 31 (P₇=BOM, P₁₃=TBS,R=H).

[0308] Ketone 32. To a solution of benzoate 31 (P₇=BOM, P₁₃=TBS, R=H)(18 mg, 0.235 mmole) and 4-methylmorpholine N-oxide (18 mg, 0.154 mmole)in CH₂Cl₂ (2.6 mL) at room temperature was added tetrapropylammoniumperruthenate (6 mg, 0.017 mmole). The solution was stirred at roomtemperature for 15 min and filtered through silica gel with 30% ethylacetate/hexane. The filtrate was concentrated under reduced pressure toyield ketobenzoate 32 (P₇=BOM, P₁₃=TBS) (18 mg, 100%).

[0309] 32 (P₇=MOP, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ 0.12 (s, 3H, TBSCH₃), 0.16 (s, 3H, TBS CH₃), 0.94 (s, 9H, TBS t-Bu), 1.25 (s, 3H, CH₃ ),1.42 (s, 3H, CH₃ ), 1.44 (s, 6H, MOP CH₃), 1.49 (s, 3H, CH₃ ), 1.75 (s,1H, OH1), 1.76 (m, 1H, H6), 1.83 (s, 3H, CH₃ 18), 2.21 (dd, J=7, 15 Hz,1H, H14), 2.25 (s, 3H, OAc), 2.29 (dd, J=8, 15 Hz, 1H, H14), 2.61 (d,J=16 Hz, 1H, H9), 2.74 (ddd, J=8, 9, 17 Hz, 1H, H6), 3.19 (s, 3H, MOPOCH₃), 3.20 (d, J=6 Hz, 1H, H3α), 3.32 (d, J=16 Hz, 1H, H9), 3.78 (dd,J=8, 10 Hz, 1H, H7), 4.15 (d, J=8 Hz, 1H, H20), 4.34 (d, J=8 Hz, 1H,H20), 4.89 (d, J=9 Hz, 1, H5), 5.04 (m, 1H, H13), 5.90 (d, J=6 Hz, 1H,H2), 7.50 (m, 2H, PhCOO-m), 7.62 (m, 1H, PhCOO-p), 8.24 (m, 2H,PhCOO-o).

[0310] 32 (P₇=TES, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ 0.12 (s, 3H, TBSCH₃), 0.16 (s, 3H, TBS CH₃), 0.65 (q, J=8 Hz, 3H, TES CH₃), 0.66 (q, J=8Hz, 3H, TES CH₃), 0.94 (s, 9H, TBS t-Bu), 1.00 (t, J=8 Hz, 3H, TES CH₂),1.24(s, 3H, CH₃ ), 1.38 (s, 3H, CH₃ ), 1.49 (s, 3H, CH₃ ), 1.75 (s, 1H,OH1), 1.80 (m, 1H, H6), 1.81 (s, 3H, CH₃ 18), 2.20 (dd, J=9, 15 Hz, 1H,H14), 2.26 (s, 3H, OAc CH₃), 2.29 (dd, J=8, 15 Hz, 1H, H14), 2.48 (ddd,J=8, 9, 17 Hz, 1H, H6), 2.58 (d, J=17 Hz, 1H, H9), 3.15 (d, J=6Hz, 1H,H3α), 3.36 (d, J=17 Hz, 1H, H9), 3.79 (dd, J=7, 9 Hz, 1H, H7), 4.14 (d,J=8 Hz, 1H, H20), 4.33 (D, J=8 Hz, 1H, H20), 4.90 (d, J=9 Hz, 1H, H5),5.04 (m, 1H, H13), 5.90 (d, J=6 Hz, 1H, H2), 7.49 (m, 2H, PhCOO-m), 7.61(m, 1H, PhCOO-p), 8.13 (m, 2H, PhCOO-o).

[0311] 32 (P₇=BOM, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃); δ 0.16 (s, 3H, TBSCH₃), 0.18 (s, 3H, TBS CH₃), 0.94 (s, 9H, TBS t-Bu), 1.26 ( s, 3H, CH₃17), 1.47 (s, 3H, CH₃ 19), 1.52 (s, 3H, CH₃ 16), 1.76 (s, 1H, OH1), 1.83(d, 3H, J=0.5 Hz, CH₃ 18), 1.89 (ddd, J=15.0, 9.5, 1.5 Hz, 1H, H6β),2.21 (dd, J=15.0, 9.0 Hz, 1H, H 14β), 2.26 (s, 1H, OAc 4), 2.29 (dd,J=15.0, 8.0 Hz, 1H, H14α), 2.72 (m, 1H, H6α), 2.75 (d, J=16 Hz, 1H,H9a), 3.18 (d, J=6.5 Hz, 1H, H3α), 3.26 (d, J=16.5 Hz, H9α), 3.65 (dd,J=9.0, 7.5 Hz, 1H, H7a), 4.15 (d, J=7.5 Hz, 1H, H20β), 4.34 (d, J=7.5Hz, 1H, H20α), 4.61 (d,J=12.0 Hz, 1H, PhCH₂O), 4.72 (d, J=12.0 Hz, 1H,PhCH₂O), 4.81 (d, J=7.0 Hz, 1H, OCH₂O), 4.92 (d, J=7.0 Hz, 1H, OCH₂O),4.93 (br d, J=6.5 Hz, 1H, H5α), 5.05 (br t, J=6.5 Hz, 1H, H13β), 5.91(d, J=6.0 Hz, 1H, H2β), 7.28 (m, 1H, PhCH₂O), 7.35 (m, 4H, PhCH₂O), 7.50(m, 2H, PhCOO-m), 7.62 (m, 1H, PhCOO-p), 8.13 (m, 2H, PhCOO-o)

[0312] Hydroxyketone 33. To a THF (1.3 mL) solution of 32 (P₇=BOM,P₁₃=TBS) (16.2 mg, 0.02 mmol) at −78° C. was added 4 equivalents of a0.24M t -BuOK solution in THF (0.33 mL, 0.08 mmol.). The solution waswarmed to −20° C. for 40 min and then briefly warmed to 0° C. beforebeing cannulated into a 0° C. THF (1.3 mL) suspension ofbenzeneseleninic anhydride (57 mg, 0.16 mmol.). The reaction was stirredfor 40 min. at 0° C. before being diluted with 20 mL of ethyl acetateand poured into 50 mL of aqueous saturated NaHCO₃. The organic layer wasthen washed with 50 mL of aqueous saturated Na₂S₂O₃ followed by 50 mL ofaqueous saturated NaHCO₃. The organic layer was then dried with Na₂SO₄,filtered and evaporated to give 18.8 mg of the hydroxyketone as an oil.To a THF (1.3 mL) solution of the crude hydroxyketone (18.8 mg) wasadded 0.33 mL of a 0.24M solution of t -BuOK (0.08 mmol) at −78° C. Thereaction was stirred 20 min. and then 0.25 mL of a 0.8M AcOH/THFsolution was added at −78° C. and stirred 5 min. The mixture was dilutedwith 20 mL of ethyl acetate and was poured into 50 mL of aqueoussaturated NaHCO₃. The organic layer was then dried with Na₂SO₄, filteredand evaporated to give 18.6 mg of a yellow solid which was then plugfiltered through silica gel with 2% ethyl acetate/hexanes followed by30% ethyl acetate/hexanes to give 15.9 mg of 33 (P₇=BOM, P₁₃=TBS) (96%yield).

[0313] 33 (P₇=BOM, P₁₃=TBS): m.p. 234-236° C., ¹H NMR (500 MHz, CDCl₃) δ0.13 (s, 3H, TBS CH₃), 0.15 (s, 3H, TBS CH3), 0.95 (s, 9H, TBS t-Bu),1.11 (s, 3H, CH₃ 16), 1.18 )s, 3H, CH₃ 17), 1.59 (s, 1H, OH1), 1.82 (s,3H, CH₃ 18), 1.89 (ddd, J=2.1, 12.4, 14.4 Hz, 1H, H6β), 1.97 (d, J=2.0Hz, 3H, CH₃ 18), 2.14 (dd, J=8.6, 15.4 Hz, 1H, H14β), 2.21 (dd, J=8.9,15.4 Hz, 1H, H14α), 2.29 (s, 3H, Ac), 2.70 (ddd, J=6.5, 9.6, 14.4 Hz,1H, H6α), 3.93 (d, J=6.9 Hz, 1H, H3α), 4.17 (d, J=8.6 Hz, 1H, H20β),4.28 (d, J=2.4 Hz, 1H, OH10β), 4.31 (dd, J=6.5, 12.4 Hz, 1H, H7α), 4.32(d, J=8.6 Hz, 1H, H20α), 4.45 (d, J=12.2 Hz, 1H, PhCH₂O), 4.60 (d,J=12.2 Hz, 1H, PhCH₂O), 4.60 (d, J=7.3 Hz, 1H, OCH₂O), 4.73 (d, J=7.3Hz, 1H, OCH₂O), 4.97 (dd, J=2.1, 9.6 Hz, 1H, H5α), 5.01 (ddd, J=2.0,8.6, 8.9 Hz, 1H, H13β), 5.35 (d, J=2.4 Hz, 1H, H10α), 5.64 (d, J=6.9 Hz,1H, H2β), 7.3 (m, 5H, PhCH₂), 7.49 (tt, J=1.7, 7.9 Hz, 2H, PhCOO-m),7.61 (tt, J=1.7, 7.6 Hz, 1H, PhCOO-p), 8.10 (dd, J=1.2, 7.9 Hz,PhCOO-o).

[0314] 33 (P₇=MOP, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ 0.13 (s, 3H, TBSCH₃), 0.15 (s, 3H, TBS CH₃), 0.95 (s, 9H, TBS t-Bu), 1.00 (s, 3H, CH₃16), 1.09 (s, 3H, CH₃ 17), 1.23 (s, 3H, MOP CH₃), 1.37 (s, 3H, MOP CH₃),1.58 (s, 1H, OH1), 1.79 (s, 3H, CH₃ 19), 1.90 (ddd, J=2.6, 8.8, 13.7 Hz,1H, H6β), 2.04 (s, 3H, CH₃ 18), 2.13 (dd, J=8.8, 15.5 Hz, 1H, H14β),2.22 (dd, J=8.8, 15.5 Hz, 1H, H14α), 2.29 (s, 3H, OAc), 2.79 (ddd, 6.3,9.9, 14.8 Hz, 1H, H6α), 3.17 (s, 3H, MOP OCH₃), 3.90 (d, J=7.1 Hz, 1H,H3α), 4.16 (d, J=8.2 Hz, 1H, H20α), 4.25 (d, J=2.2 Hz, 1H, OH4), 4.32(d, J=8.8 Hz, 1H, H20β), 4.41 (dd, J=6.6, 11.0 Hz, 1H, H7α), 4.94 (dd,J=2.2, 9.9 Hz, 1H, H5α), 5.03 (ddd, J=1.1, 8.2, 8.8 Hz, 1H, H13β), 5.20(d, J=6.2 Hz, 1H, H10α), 5.60 (d, J=7.2 Hz, 1H, H2β), 7.48 (t, J=7.7 Hz,2H, PhCOO-m), 7.61 (t, J=7.7 Hz, 1H, PhCOO-p), 8.10 (d, J=7.1 Hz, 2H,PhCOO-o).

[0315] Acetate 34. To a pyridine (0.1 mL) solution of 33 (P₇=BOM,P₁₃=TBS) (15.9 mg, 0.02 mmol) and DMAP (1.2 mg, 0.01 mmol) at roomtemperature was added acetic anhydride (38 μL, 0.4 mmol) and thereaction stirred 19 h. The mixture was then diluted with 20 mL of ethylacetate and poured into 50 mL of aqueous saturated NaHCO₃. The organiclayer was dried with Na₂SO₄, filtered and evaporated to give 18.1 mg ofcrude product. The material was plug filtered through silica gel with20% ethyl acetate/hexanes to give 16.8 mg of 34 (P₇=BOM, P₁₃=TBS) (100%yield).

[0316] 34 (P₇=BOM, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃) δ 0.14 (s, 3H, TBSMe), 0.16 (s, 3H, TBS Me), 0.95 (s, 9H, TBS t-Bu), 1.17 (s, 3H, CH₃ 17),1.18 (s, 3H, CH₃ 16), 1.63 (s, 1H, OH1), 1.76 (s, 3H, CH₃ 19), 1.99(ddd, J=2.1, 10.6, 14.7 Hz, 1H, H6β), 2.04 (d, J=1.0 Hz, 3H, CH₃ 18),2.17 (dd, J=8.6, 15.1 Hz, 1H, H14β), 2.19 (s, 3H, AcO10), 2.24 (dd,J=8.6, 15.1 Hz, 1H, H14α), 2.28 (s, 3H, AcO4), 2.88 (ddd, J=6.5, 9.8,14.7 Hz, 1H, H6a), 3.87 (d, J=7.0 Hz, 1H, H3α), 4.15 (d, J=8.2 Hz, 1H,H20β), 4.24 (dd, J=6.5, 10.6 Hz, 1H, H7α), 4.31 (d, J=8.2 Hz, 1H, H20α),4.44 (d, J=12.0 Hz, 1H, PhCH₂O), 4.68 (d, J=12.0 Hz, 1H, PhCH₂O), 4.85(s, 2H, OCH₂O), 4.95 (dd, J=2.1, 9.8 Hz, 1H, H5α), 5.65 (d, J=7.0 Hz,1H, H2β), 6.39 (s, 1H, H10α), 7.30 (m, 5H, PhCH₂), 7.49 (tt, J=1.4, 8.2Hz, 2H, PhCOO-m), 7.61 (tt, J=1.4, 7.2 Hz, 1H, PhCOO-p), 8.05 (dd,J=1.2, 8.2 Hz, 1H, PhCOO-o), IR (CHCl₃) υ 3600, 3050, 2975, 2880, 1750,1730, 1460, 1379, 1250, 1100, 1020, 860 cm^(−1.)

[0317] 34 (P₇=P₁₃=TES): ¹H NMR (300 MHz, CDCl₃) δ 0.57 (q, J=7.7 Hz, 6H,TES CH₂), 0.67 (q, J=7.7 Hz, TES CH₂), 0.92 (t, J=7.7 Hz, 9H, TES CH₃),1.01 (t, J=7.7 Hz, 9H, TES CH₃), 1.11 (s, 3H, CH₃ 17), 1.19 (s, 3H, CH₃19), 1.61 (s, 1H, OH1), 1.67 (s, 3H, CH₃ 16), 1.86 (ddd, J=2.2, 10.4,14.3 Hz, 1H, H6β), 2.11 (d, J=1.1 Hz, 3H, CH₃ 18), 2.12 (m, 1H, H14β),2.17 (s, 3H, OAc10), 2.23 (dd, J=7.6, 14.9 Hz, 1H. H14α), 2.28 (s, 3H,OAc4), 2.51 (ddd, J=6.9, 9.6, 14.3 Hz, 1H, H6α), 3.82 (d, J=7.2 Hz, 1H,H3α), 4.14 (d, J=8.3 Hz, 1H, H20β), 4.30 (d, J=8.3 Hz, 1H, H20α), 4.48(dd, J=6.6, 10.4 Hz, 1H, H7α), 4.92 (dd, J=7.7, 8.8 Hz, 1H, H5α), 4.96(d, J=8.2 Hz, 1H, H13β), 5.63 (d, J=6.6 Hz, 1H, H2α), 6.47 (s, 1H,H10α), 7.47 (t, J=7.1 Hz, 2H, PhCOO-m), 7.60 (t, J=` 7.1 Hz, PhCOO-p),8.10 (d, J=7.1 Hz, PhCOO-o).

[0318] Diol 35. A solution of 34 (P₇=BOM, P₁₃=TBS) (16.3 mg, 0.0199mmol) in THF (0.5 mL) was added totris(diethylamino)sulfoniumdifluorotrimethylsilicate (TASF) (37 mg,0.134 mmole) at room temperature under nitrogen atmosphere. The solutionwas stirred for 40 min, diluted with ethyl acetate, poured into 20 mL ofa saturated aqueous NaHCO₃ solution and extacted with CHCl₃ (30 mL ×3).The combined organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give 16 mg of a pale yellow oil,which was filtered through a pad of silica gel using 70% ethylacetatelhexane as eluent. The filtrate was concentrated to yield 13.5 mg(94%) of 7-BOM BIII (35).

[0319] 3 5(P₇=BOM) mp. 224-225° C., ¹H NMR (500 MHz, CDCl₃), δ 1.08(s,3H, CH₃ 17), 1.18 (s, 3H, CH₃ 16), 1.61(s, 1H, OH1), 1.77 (s, 3H, CH₃19), 1.99 (ddd, J=2, 10.5, 14.5 Hz, 1H, H6β), 2.02 (d, J=5 Hz, 1H,OH13), 2.10 (d, J=1.5 Hz, 3H, CH₃ 18), 2.20(s, 3H, AcO), 2.28 (s, 3H,AcO), 2.27-2.29(m, 2H, H14), 2.89 (ddd, J=7, 10, 16.5 Hz, 1H, H6α), 3.94(d, J=7 Hz, 1H, H3), 4.16 (dd, J=1, 8.5 Hz, 1H, H20β), 4.24 (dd, J=6.5,10.5 Hz, 1H, H7), 4.31 (d, J=8 Hz, 1H, H20α), 4.45 (d, J=12.0 Hz, 1H,OCH₂Ph), 4.67 (d, J=12.0 Hz, 1H, OCH₂Ph), 4.84 (d, J=5 Hz, 1H, OCH₂O),4.86 (d, J=5 Hz, 1H, OCH₂O), 4.87 (m, 1H, H13β), 4.95 (dd, J=2.0, 9.5Hz, 1H, H5α), 5.63 (d, J=7 Hz, 1H, H2β), 6.40 (s, 1H, H10α), 7.30 (m,5H, PhCH₂), 7.48 (m, 2H, PhCOO-m), 7.61 (m, 1H, PhCOO-p), 8.10 (2H, m,PhCOO-o). ¹³C NMR (CDCl₃) δ (ppm) 10.3, 14.9, 20.0, 20.7, 22.4, 26.6,35.3, 38.4, 42.7, 47.2, 57.4, 67.8, 69.9, 74.6, 75.8, 76.4, 78.7, 80.3,80.3, 80.9, 84.4, 96.7, 127.7, 127.9, 128.5, 128.8, 129.6, 130.3, 132.4,133.8, 138.0, 144.4, 167.3, 169.8, 171.0, 203.0. IR (CHCl₃) υ 1720, 1460cm⁻¹. Anal. Calcd. for C₃₉H₄₆O₁₂: C, 66.28; H, 6.56. Found C, 66.09; H,6.59.

[0320] 7-BOM-Taxol. To a solution of 7-BOM baccatin III (35) (13.2 mg,0.018 mmol) in 0.25 mL of THF at −45° C. was added dropwise 21 μL of a1.03 M solution of lithium bis(trimethylsilyl)amide in THF. After 1 h at−45° C., a solution of(S)-cis-1-benzoyl-3-triethylsilyloxy-4-azetidin-2-one 15 mg, 0.039 mmol)in 0.25 mL of THF was added dropwise to the mixture. The solution waswarmed to 0° C. and kept at that temperature for 1 h before 0.2 mL of a10% solution of AcOH in THF was added. The mixture was partitionedbetween saturated aqueous NaHCO₃ and 60% ethyl acetate/hexane.Evaporation of the organic layer gave a residue which was purified byfiltration through silica gel to give 20.2 mg of crude(2′R,3′S)-2′-triethylsilyl-7-BOM taxol.

[0321] To a solution of 20.2 mg (0.018 mmol) of(2′R,3′S)-2′-triethylsilyl-7-BOM taxol in 0.8 mL of acetonitrile and 0.3mL of pyridine at 0° C. was added 0.10 mL of 48% aqueous HF. The mixturewas stirred at 0° C. for 1 h and then partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 17.7 mg of material which was purified by flashchromatography to give 15.4 mg (86%) of 7-BOM-taxol.

[0322] 7-BOM-Taxol: m.p 169-172° C., ¹H NMR (CDCl₃, 300 MHz) δ 8.11 (d,J=7.1 Hz,2H, benzoate ortho), 7.76 (d, J=7.1 Hz,1H, benzamide ortho ),7.61−7.26 (m, 11 H, aromatic), 7.06(d, J=8.8 Hz, 1H, NH), 6.33 (s, 1H,H10), 6.17 (dd, J=8.8, 8.8 Hz, 1H, H13), 5.79 (dd, J=8.8, 2.2 Hz, 1H,H3′), 5.67 (d, J=6.6 Hz, 1H, H2b), 4.91 (d, J=8.8 Hz,1H, H5),4.87−4.77(m, 3H, H2′, OCH2Ph),4.67(d, J=12Hz, OCH20) 4.43(d, J=12 Hz,OCH20), 4.30 (d, J=8.2 Hz, 1H, H20α), 4.19 (d, J=8.2 Hz, 1H, H20b), 4.15(m, 1H, H7), 3.70 (d, J=6.6 Hz, 1H, H3), 3.61 (d, J=2.5 Hz, 1H, 2′OH),2.85 (m, 1H, H6a), 2.35 (s, 3H, 4Ac), 2.30 (m, 2H, H14), 2.19 (s, 3H,10Ac), 2.05 (m, 1H, H6b), 1.78 (br s, 6H, Me18,Me19), 1.72 (s, 1H, 10H),1.19 (br s, 6H, Me16, Me17). Anal. Calcd. for C₅₅H₅₉O₁₅×0.5H₂O: C,67.20; H, 6.15. Found C, 67.08; H, 6.16.

[0323] Taxol. To a suspension of 10% Pd on carbon (50 mg) in ethanol(0.6 mL) saturated with hydrogen at room temperature was added asolution of 7-BOM-taxol (14.4 mg, 0.0148 mmol) in ethanol (0.2 mL ×4).The reaction mixture was refluxed for 45 min under hydrogen and thenfiltered through silica gel eluting with ethyl acetate. The solvent wasevaporated under reduced pressure to give 11.9 mg of taxol (94%) ascolorless needles, which exhibited spectra identical with an authenticsample of taxol.

[0324] Taxol: mp. 210-212° C., ¹H NMR (500 MHz, CDCl₃) δ 1.15 (s,3H, CH₃16), 1.24 (s, 3H, CH₃ 17), 1.68 (s, 3H, CH₃ 19), 1.75 (s, 1H, OH1),1.79(s, 3H, CH₃ 18), 1.90 (ddd, J=14.6, 11.0, 2.3 Hz, 1 H, H6β), 2.26(s, 3H, AcO10), 2.33 (dd, J=15.4, 8.9 Hz, 1H, H14β), 2.38 (dd, J=15.4,8.9 Hz, 1H, H14α), 2.41 (s, 3H, AcO4), 2.46 (d, J=4.1 Hz, 1H, OH7), 2.57(ddd, J=10.0,14.6,6.5 Hz, 1H, H6α), 3.54 (d, J=5.0 Hz, 1H, OH2′), 3.82(d, J=6.9 Hz, 1H, H3α), 4.22 (d, J=8.5 Hz, 1H, H20α), 4.32 (d, J=8.5 Hz,1 H, H20β), 4.42 (ddd, J=11.0, 6.5, 4.1 Hz, 1 H, H7α), 4.81 ( dd, J=5.0,2.5 Hz, 1 H, H2′), 4.96 (dd, J=10.0, 2.3 Hz, 1H, H5α), 5.69 (d, J=6.9Hz, 1 H, H2β), 5.81 (dd, J=8.7, 2.5 Hz, 1 H, H3′), 6.25 (dd, J=8.9, 8.9Hz, 1 H, H13β), 6.29 (s, 1H, H 10α), 6.98 (d, J=8.7 Hz, 1H, NH),7.37 (m,1H, phCON -p), 7.46 (m, 9 H, Ph 3′, PhCOO 2′ -m, PhCON -m), 7.62 (m, 1H,PhCOO-p), 7.76 (br d, J=8.7 Hz, 1H, PhCON-o), 8.16 (br d, J=7.3 Hz, 1 H,PhCOO-o). IR (CHCl₃) υ 1730, 1650 cm⁻¹.

[0325] 10 -Deacetyl baccatin II (36). To a mixture of ketone 33 (P₇=MOP,P₁₃=TES) (2.2 mg, 0.003 mmol) in pyridine (30 μL, 0.36 mmol) andacetonitrile (20 μL) at 0° C. was added 48% aqueous HF (12 μL, 0.32mmol) and the solution was then warmed to room temperature and stirredfor 36 hours. The mixture was then diluted with 2 mL of ethyl acetateand poured in to a separatory funnel containing 30 mL of aqueoussaturated Na₂CO₃ and 20 mL ethyl acetate. The aqueous layer wasextracted twice with 20 mL of ethyl acetate and the organic layers werecombined, dried with Na₂SO₄, filtered, and concentrated to give 2.7 mgof a yellow oil. The material was purified by plug silica gel columnchromatography by eluting with a 50% ethyl acetate/hexanes mixturefollowed by ethyl acetate to give 1.5 mg of 36, which exhibited spectraidentical with an authentic sample of 10-DAB.

[0326] Baccatin III (37). To a mixture of ketone 34 (P₇=MOP) (2.1 mg,0.003 mmol) in pyridine (30 μL, 0.36 mmol) and acetonitrile (20 μL) at0° C. was added 48% aqueous HF (12 μL, 0.32 mmol) and the solution wasthen warmed to room temperature and stirred for 36 hours. The mixturewas then diluted with 2 mL of ethyl acetate and poured in to aseparatory funnel containing 30 mL of aqueous saturated Na₂CO₃ and 20 mLethyl acetate. The aqueous layer was extracted twice with 20 mL of ethylacetate and the organic layers were combined, dried with Na₂SO₄,filtered, and concentrated to give 2.7 mg of a yellow oil. The materialwas purified by plug silica gel column chromatography by eluting with anethyl acetate/hexanes mixture to give 1.7 mg of 37, which exhibitedspectra identical with an authentic sample of baccatin III.

REACTION SCHEME A′

[0327] Hydroxyketone 19. To a vigorously stirred solution of ketone 18(P₇=MOP) (181 mg, 0.265 mmol) in TBF (2.2 mL) under nitrogen at −78° C.was added dropwise down the side of the flask 2.13 mL of a 0.2 Msolution (0.426 mmol) of LDA in THF. After 10 min, a solution of 116 mgof (S)-camphorsulfonyloxaziridine (116 mg, 0.396 mmol) in 1.5 mL THF wasadded dropwise down the side of the flask. The reaction mixture wascooled to −40° C. and, after stirring 1 h, 2 mL of a saturated aqueousNaHCO₃ solution was added. The reaction mixture was diluted with 50 mLof 30% ethyl acetate in hexanes and washed with 20 mL of a saturatedaqueous NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting oil was filteredthrough silica gel with 30% ethyl acetate in hexanes and concentrated togive 210 mg of a colorless oil. This material was purified by radialchromatography, eluting with 25% ethyl acetate in hexanes to yield 150mg (81%) 5β-hydroxyketone 19 as a white solid, 15 mg (8%) returnedstarting ketone 18 and 10 mg (5%) of the corresponding 5ac-hydroxyketone.

[0328] 19 (P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.08 (s, 3H, TBS CH₃),0.12 (s, 3H, TBS CH₃), 0.62 (q, J=8.2 Hz, 6H, TES CH₂), 0.90 (s, 9H, TBSt-Bu), 0.96 (t, J=8.2 Hz, 9H, TES CH₃), 1.05 (s, 3H, CH₃ 19), 1.19 (s,3H, CH₃ 17), 1.33 (s, 3H, CH₃ 16), 1.35 (s, 3H, MOP CH₃), 1.43 (s, 3H,MOP CH₃), 1.67 (dd, J=5.0, 14.7 Hz, 1H, H9β), 1.87 (m, 1H, H6β), 2.12(dd, J=4.1, 15.1 Hz, 1H, H14α), 2.14 (d, J=1.4 Hz, 3H, CH₃ 18), 2.23(dd,J=7.3, 14.7 Hz, 1H, H9α), 2.55 (dd, J=9.2, 15.1 Hz, 1H, H14β), 2.76(ddd, J=3.7, 7.3, 13.7 Hz, 1H, H6α), 3.22 (s, 3H, MOP OCH₃), 3.24 (d,J=4.1 Hz, 1H, OH5), 3.28 )d, J=6.0 Hz, 1H, H3α), 3.83 (dd, J=3.7, 9.2Hz, 1H, H7α), 4.06 (ddd, J=4.1, 7.3, 7.3 Hz, 1H, H5α), 4.46 (dd, J=5.0,7.3 Hz, 1H, H10β), 4.53 (d, J=6.0 Hz, 1H, H2β), 4.63 (dd, J=2.8, 9.2 Hz,1H, H13β).

[0329] Ketone 20. To a vigorously stirred solution of 5-hydroxy-4-ketone19 (P₇=MOP) (420 mg, 0.602 mmol) in CH₂Cl₂ (20 mL) and triethylamine(1.18 mL, 8.5 mmol) under nitrogen at 0° C. was addedtrimethylsilylchloride (0.40 mL, 3.3 mmol). After 0.5 h, the reactionmixture was quenched with 5 mL of a saturated aqueous NaHCO₃ solutionand extracted with 50 mL CHCL₃. The organic phase was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive 453 mg (98%) of ketone 20 as a colorless oil. This material wasused without further purification.

[0330] 20 (P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.11 (s, 6H, TBS CH₃),0.12 (s, 9H, TMS CH₃), 0.59 (q, J=7.8 Hz, 6H, TES CH₂), 0.94 (s, 9H, TBSt-Bu), 0.96 (t, J=7.8 Hz, 9H, TES CH₃), 1.23 (s, 3H, CH₃ 17), 1.32 (s,3H, CH₃ 19), 1.33 (s, 3H, MOP CH₃), 1.35 (s, 3H, CH₃ 16), 1.37 (s, 3H,MOP CH₃), 1.86 (m, 3H, H6β, H9α, H9β), 2.05 (d, J=1.4 Hz, 3H, CH₃ 18 ),2.43 (d, J=3.7 Hz, 1H, H14β), 2.45 (d, J=4.6 Hz, 1H, H14α), 2.59 (ddd,J=6.0, 8.2, 14.2 Hz, 1H, H6α), 2.84 (d, J=6.0 Hz, 1H, H3α), 3.21 (s, 3H,MOP OMe), 3.51 (dd, J=6.0, 11.0 Hz, 1H, H7α), 3.94 (dd, J=4.1, 8.2 Hz,1H, H5α), 4.38 (dd, J=5.0, 8.7 Hz, 1H, H10β), 4.54 (d, J=6.0 Hz, 1H,H2β), 4.74 (dd, J'6.4, 6.4 Hz, 1H, H13β).

[0331] Diol 21. To a stirred solution of ketone 20 (P₇=MOP) (453 mg,0.588 mmol) in THF (23 mL) under nitrogen at −78° C. was added dropwise1.95 mL of a 3 M solution of MeMgBr in ether (5.85 mmol). The reactionmixture was stirred for 5.5 h, poured into 100 mL of a saturated aqueousNaHCO₃ solution and extracted with three 100 mL portions of CHCl₃. Thecombined organic phases were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to yield 453 mg of the hydroxytrimethylsilyl ether as a colorless oil. This material was used withoutfurther purification.

[0332] To a stirred solution of the trimethylsilyl ether (453 mg) inpyridine (8 mL) and acetonitrile (8 mL) at 0° C. was added 0.8 mL of a48% aqueous HF solution. After stirring 20 min, the resulting mixturewas poured into 100 mL of a saturated aqueous NaHCO₃ solution andextracted with three 150 mL portions of CHCl₃. The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to yield 422 mg of diol 21. This material used without furtherpurification.

[0333] 21 (P₇=MOP): ¹H NMR (300 MHz, CDCl₃) δ 0.08 (s, 3H, TBS CH₃),0.10 (s, 3H, TBS CH₃), 0.56 (q, J=7.7 Hz, 6H, TES CH₂), 0.90 (s, 9H, TBSt-Bu), 0.93 (t, J=7.7 Hz, 9H, TES CH₃), 1.16 (s, 3H, CH₃ 17), 1.25 (s,3H, CH₃ 16), 1.29 (s, 3H, CH₃ 19) 1.31 (s, 3H, CH₃ 20 ), 1.38 (s, 3H,MOP CH₃), 1.46 (s, 3H, MOP CH₃), 1.81 (d, J=3.8 Hz, 1H, H3α), 1.86 (d,J=9.9 Hz, 1H, H9β), 1.90 (dd, J=6.1, 8.3 Hz, 1H, H9α), 1.96 (s, 3H, CH₃18), 2.12 (ddd, J=3.3, 3.3, 10.4 Hz, 1H, H6α), 2.30 (m, 1H, H6β), 2.42(dd, J=3.9, 15.4 Hz, 1H, H14α), 2.61 (dd, J=9.3, 15.4 Hz, 1H, H14β),2.81 (s, 1H, OH4), 3.04 (m, 1H, OH5), 3.40 (dd, J=3.9, 15.8 Hz, 1H,H7α), 4.28 (dd, J=6.6, 8.2 Hz, 1H, H10β), 4.62 (dd, J=1.6, 7.8 Hz, 1H,H13β), 4.66 (d, J=3.8, 1H, H2β).

[0334] Acetate 22. To a stirred solution of diol 21 (P₇=MOP) (470mg,0.66 mmol) in pyridine (12 mL) under nitrogen at room temperature wasadded acetic anhydride (4.5 mL). After 11 h, the reaction mixture wasdiluted with 50 mL of CHCl₃, then poured into 50 mL of saturated aqueoussodium bicarbonate solution. The aqueous phase was extracted with CHCl₃then the combined extracts were washed with brine, dried with Na₂SO₄ andfiltered. Concentration of the filtrate under vacuum yielded 470 mg (94%from 20 ) of crude material which was pure acetate 22 by ¹H NMR and TLCanalysis.

[0335] 22 (P₅=Ac, P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.10(s, 3H, TBSCH₃), 0.13 (s, 3H, TBS CH₃), 0.59 (q, J=7.8 Hz, 6H, TES CH₂), 0.94 (s,9H, TBS t-Bu), 0.95 (t, J=7.8 Hz, 9H, TES CH₃), 1.18 (s, 3H, CH₃ 17),1.30 (s, 3H, CH₃ 16), 1.32 (s, 3H, CH₃ 19), 1.33 (s, 6H, CH₃ 20, MOPCH₃), 1.41 (s, 3H, MOP CH₃), 1.91 (d, J=3.4 Hz, 1H, H3α), 1.94 (m, 2H,H9, H9), 2.00 (d, J=1.5 Hz, 3H, CH₃ 18), 2.06 (ddd, J=3.9, 3.9, 11.7 Hz,1H, H6α), 2.10 (s, 3H, OAc), 2.14 (dd, J=11.7, 23.9 Hz, 1H, H6β), 2.38(dd, J=3.9, 15.1 Hz, 1H, H14α), 2.63 (dd, J=9.3, 15.1 Hz, 1H, H14β),2.78 (d, J=1.5 Hz, 1H, OH4), 3.20 (s, 3H, OMe CH₃), 3.38 (dd, J=3.9,11.7 Hz, 1H, H7α), 4.30 (dd, J=4.9, 10.3 Hz, 1H, H10β), 4.50 (ddd,J=1.5, 3.9, 12.2 Hz, 1H, H5α), 4.64 (dd, J=1.5, 1.5 Hz, 1H, H13β), 4.66(d, J=3.4 Hz, 1H, H2β).

[0336] Olefin 23. To a stirred solution of alcohol 22 (P₅=Ac, P₇=MOP)(26 mg, 0.034 mmol) in CH₂Cl₂ (1.48 mL) and pyridine (0.37 mL) undernitrogen at 10° C. was added SOCl₂(0.037 mL, 5.1 mmol) over a period ofthree minutes. The mixture was warmed to room temperature and stirredfor 2.3 h then diluted with CHCl₃ and poured into saturated aqueoussodium bicarbonate solution. The aqueous phase was extracted with CHCl₃and the combined extracts were washed with brine, dried over anhydrousNa₂SO₄ and filtered. Concentration of the filtrate under vacuum yielded24 mg of crude material which was purified by silica gel chromatographyto give 13 mg (52%) of a 4:1 mixture of 7-MOP-exo;endo cyclic olefinsand 6 mg (27%) of a 4:1 mixture of 7-hydroxy-exo;endo cyclic olefins.

[0337] 23 (P₅=Ac, P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s, 3H, TBSCH₃), 0.12 (s, 3H, TBS CH₃), 0.59 (q, J=7.9, 6H, TES CH₂), 0.93 (s, 9H,TBS t-Bu), 0.96 (t, J=7.9, (H, TES CH₃), 1.21 (s, 3H, CH₃ 17), 1.30 (s,3H, CH₃ 19), 1.32 (s, 3H, MOP CH₃), 1.34 (s, 3h, MOP CH₃), 1.37 (s, 3H,CH₃ 16 ), 1.72 (m, 2H, H6β, H9β), 1.89 (dd, J=3.8, 13.4 Hz, 1H, H9β),2.03 (d, J=1.37 Hz, 3H, CH₃ 18 ), 2.05 (s, 3H, OAc CH₃), 2.33 (dd,J=5.1, 15.4 Hz, 1H, H14α), 2.47 (m, 2H, H6α, H14β), 3.06 (d, J=5.8 Hz,1H, H3α), 3.20 (s, 3H, MOP OMe), 3.38 (dd, J=6.9, 11.0 Hz, 1H, H7α),4.37 (dd, J=3.8, 11.0 Hz, 1H, H10β), 4.53 (d, J=5.8 Hz, 1H, H2β), 4.74(m, 1H, H13β), 5.15 (s, 1H, H20E), 5.21 (d, J=1.37 Hz, 1H, H20Z), 5.36(d, J=9.3 Hz, 1H, H5α).

[0338] Diol 24. To a stirred solution of a 4:1 mixture of theexo,endocyclic olefins 23 (P₅=Ac, P₇=MOP) (249 mg, 0.337 mmol) inpyridine (4.6 mL) under nitrogen at 0° C. was added 2.35 mL of a 0.157 Msolution (0.368 mmol) of OSO₄ in THF. After 1 h, NaHSO₃ was added alongwith 6.2 mL of water and the mixture was stirred for 1 h at roomtemperature. The mixture was then diluted with ethyl acetate and pouredinto saturated aqueous sodium bicarbonate. The aqueous layer wasextracted with ethyl acetate and the combined extracts were washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to yield 281 mg of crude material which was purified by silicagel chromatography, eluting with 50% ethyl acetate/hexane to yield 190mg (73%) of pure diol 24 and 48 mg (19%) of the enol acetate.

[0339] 24 (P₅=Ac, P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s, 3H, TBSCH₃), 0.11 (s, 3H, TBS CH₃), 0.60 (dq, J=1.5, 7.8 Hz, 6H, TES CH₂), 0.87(s, 3H, CH₃ 19), 0.93 (s, 9H, TBS t-Bu), 0.95 (t, J=7.8 Hz, 9H, TESCH₃), 1.20 (s, 3H, CH₃ 17), 1.31 (s, 3H, CH₃ 16), 1.33 (s, 3H, MOP CH₃),1.47 (s, 3H, MOP CH₃)1.54 (dd, J=12.3, 25.0 Hz, 1H, H6β), 1.63 (dd,J=5.5, 15.1 Hz, 1H, H9β), 2.05 (s, 3H, OAc), 2.15 (s, 3H, CH₃ 18), 2.26(m, 2H, H9α, OH20) 2.37 (dd, J=9.2, 14.7 Hz, 1H, H14β), 2.46 (ddd,J=4.8, 4.8, 13.4 Hz, 1H, H6α), 2.69 (d, J=4.5 Hz, 1H, H3α), 3.18 (s, 3H,MOP CH₃), 3.28 (dd, J=3.8, 14.7 Hz, 1H, H14α), 3.76 (dd, J=4.0, 11.6 Hz,1H, H7α), 3.84 (m, 2H, H20, H20), 3.95 (s, 1H, OH4), 4.42 (dd, J=5.1,5.8 Hz, 1H, H10β), 4.44 (d,J=4.1 Hz, 1H, H2β), 4.63 (dd, J=4.1, 12.3 Hz,1H, H5α), 4.67 (dd, J=4.1, 9.2 Hz, 1H, H13β).

[0340] 24 (P₇=BOM): ¹H NMR (300 MHz, CDCl₃) δ 0.9 (s, 3H, TBS CH₃), 0.10(s, 3H, TBS CH₃), 0.58 (q, J=7.9 Hz, 2H, TES CH₂), 0.83 (s, 3H, CH₃ 19),0.92 (s, 9H, TBS t-Bu), 0.93(t, J=7.9 Hz, TES CH₃), 1.20 (s, 3H, CH₃ 17), 1.33 (s, 3H, CH₃ 16), 1.58 (q, J=13.2 Hz, 1H, H6β), 1.71 (dd, J=10.4,5.5 Hz, H9β), 2.04(s, 3H, OAc), 2.17 ( br s, 3H, CH₃ 18), 2.20 (dd,J=10.4, 3.8 Hz, 1H, H9α), 2.35 (dd, J=14.8, 9.1 Hz, 1H, H14β), 2.43 (dt,J=13.2, 5.0 Hz, 1H, H6α), 2.80 (d, J=4.6 Hz, 1H, H3α), 3.31 (dd, J=4.4,14.8 Hz, 1H, H14α), 3.71 (dd, J=4.9, 13.0 Hz, 1H, H7α), 3.83 (m, 2H,H20), 3.98(s, 1H, OH1), 4.46(d, J=4.8 Hz, 1H, H2β), 4.48 (m, 1H, H10β),4.51(d, J=12.1 Hz, 1H, PhCH₂O), 4.64 (dd, J=13.2, 5.0 Hz, 1H, H5α), 4.66(m, 1H, H13β), 4.70 (d, J=12.1 Hz, 1H, PhCH₂O), 4.83 (d, J=7.1 Hz, 1H,OCH₂O), 4.94 (d, J=7.1 Hz, 1H, OCH₂O), 7.33(m, 5H, Ph).

[0341] Triol 25. To a stirred solution of acetoxydiol 24 (P₅=Ac, P₇=MOP)(26.5 mg, 0.035 mmol) in anhydrous methanol (0.9 mL) at −5° C. undernitrogen was added 0.060 mL of a 0.166 M (0.01 mmol) methanolic solutionof sodium methoxide. After 2.5 h, the reaction mixture was diluted with10 mL of ethyl acetate, then poured into 10 mL of a saturated aqueousNaHCO₃ solution. The organic phase was washed with 10 mL of a saturatedaqueous NaHCO₃ solution, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to give 25 mg of pure triol 25 (100%).

[0342] 25 (P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s, 3H, TBS CH₃),0.11 (s, 3H, TBS CH₃), 0.60 (q, J=8.06 Hz, 6H, TES CH₂), 0.87 (s, 3H,CH₃ 19), 0.94 (s, 9H, TBS t-Bu), 0.95 (t, J=8.1 Hz, 9H, TES CH₃), 1.19(s, 3H, CH₃ 17), 1.31 (s, 3H, CH₃ 16), 1.33 (s, 3H, MOP CH₃), 1.47 (s,3H, MOP CH₃), 1.59 (dd, J=11.7, 11.7 HZ, 1H, H6β), 1.62 9dd, J=5.5, 16.1HZ, 1H, H9β), 2.11 (d, J=0.7 Hz, 3H, CH₃ 18), 2.24 (dd, J=5.5, 16.1 Hz,1H, H9α), 2.38 (dd, J=9.5, 15.0 Hz, 1H, H14β), 2.45 (ddd, J=4.4, 4.4,13.6Hz, 1H, H6α), 2.60 (d, J=4.4 Hz, 1H, H3α), 3.21 (s, 3H, MOP OMe),3.25 (dd, J=4.4, 15.0 Hz, 1H, H14α), 3.52 (dd, J=4.4, 12.8 Hz, 1H, H7α),3.72 (dd, J=4.4, 11.4 Hz, 1H, H5α), 3.79 (s, 1H, OH4), 3.86 (d, J=11.0,1H, H20), 3.93 (d, J=11.4 Hz, 1H, H20), 4.42 (dd, J=5.1, 5.1 Hz, 1H,H10β), 4.45 (d, J=4.4 Hz, 1H, H2β), 4.66 (dd, J=4.0, 9.2 Hz, 1H, H13β).

[0343] p-Methoxybenzylidene acetal 25b: To a solution of the diol 24(P₅=Ac, P₇=BOM) (6.5 mg, 0.0079 mmol) and anisaldehyde dimethyl acetal(0.013 ml, 0.076 nmol) stirred in CH₂Cl₂ was added a solution ofp-toluenesulfonic acid (0.002 ml, 0.1M in THF, 0.0002 mmol). Theresulting solution was stirred at room temperature for 15 min thentriethylamine (0.1 ml) was added and stiing was continued for 10 min.The mixture was rinsed into 30% ethyl acetate in hexanes (15 ml) thenthe aqueous phase was extracted with 30% ethyl acetate in hexanes (2 x 5ml). The combined extracts were washed with brine, dried over Na₂SO₄,and filtered. Concentration of the filtrate under vacuum yielded 12 mgof colorless oil which was purified by silica gel chromatography toyield 6.9 mg (96%) of p-methoxybenzylidene acetal 25b as a 5:1 mixtureof diasteromers.

[0344] 25b (P₅=Ac, P₇=BOM, major diasteromer): ¹H NMR (500 MHz, CDCl₃) δ−0.05 (s, 3H, TBS CH₃), 0.07 (s, 3H, TBS CH₃), 0.60(q, J=7.9 Hz, 2H, TESCH₂), 0.78 (s, 3H, CH₃ 19) 0.82 (s, 9H, TBS t-Bu), 0.95(t, J=7.9 Hz, TESCH₃), 1.25 (s, 3H, CH₃ 17), 1.37 (s, 3H, CH₃ 16), 1.58 (m, H6β), 1.70(dd, J=16.8,5.8 Hz, H9β), 1.74 (s, 3H, OAc), 2.26 (s, 3H, CH₃ 18), 2.28(dd, J=16.8, 1.4 Hz, 1H, H9α), 2.38 (dd, J=15.1, 9.7 Hz, 1H, H14β), 2.57(dt, J=5.1, 9.9 Hz, 1H, H6α) 3.10 (dd, J=5.1, 14.7 Hz, 1H, H14α), 3.11(d, J=4.8 Hz, 1H, H3α), 3.79 (s, 3H, OCH₃), 3.84 (dd, J=5.0, 11.5 Hz,1H, H7α), 4.15 (d, J=8.2Hz, 1H, H20), 4.20 (d, J=8.2 Hz, 1H, H20),4.48(d, J=12.0 Hz, 1H, OCH₂Ph), 4.55 (d, J=4.8 Hz, 1H, H2β), 4.57 (m,1H, H10β), 4.71 (d, J=12.0 Hz, 1H, OCH₂Ph), 4.73 (m, 1H, H13β), 4.78(dd, J=12.4, 4.9 Hz, 1H, H5α), 4.84 (d, J=6.7 Hz, 1H, OCH₂O), 4.99 (d,J=6.7 Hz, 1H, OCH₂O), 6.05 (s, 1H, acetal CH), 6.80 (d, J=7.5 Hz, 2H,p-MeOPh -o), 7.27-7.36 (m, 7H, p-MeOPh -m and Ph).

[0345] Acetonide 26b. To a solution of the p-methoxybenzylidene acetal25b (P₅=Ac, P₇=BOM) (11.5 mg, 0.012 mmol) in 0.4 mL of toluene stirredat 0° C. was added a solution of diisobutylaluminum hydride (0.082 ml,2.0M in toluene, 0.12 mmol). The resulting solution was stirred for 3.5h then methanol (0.1 ml) was added. The mixture was diluted with ethylacetate (5 ml) and stirred with saturated aqueous sodium potassiumtartrate for 1.5 hours. The aqueous phase was separated and extractedwith ethyl acetate (2×10 ml) then the combined extracts were washed withbrine and dried with Na₂SO₄. Filtration followed by concentration of thefiltrate under vacuum yielded 12 mg of crude material that was purifiedby silica gel chromatography (30% ethyl acetate in hexanes eluent) toyield 4.7 mg of a mixture of formate acetals, 1.1 mg of4-MPM-1,2,5,20-tetraol, and 5.2 mg of a mixture of formatep-methoxybenzyl ethers.

[0346] The mixture of formate acetals was dissolved in methanol (0.1 ml)and 3 % aqueous NH₄OH was added. The cloudy mixture was stirred at roomtemperature for 30 min then rinsed into ethyl acetate over saturatedaqueous NaHCO₃. The aqueous phase was extracted with ethyl acetate (2×10ml) and the combined extracts were washed with brine, dried over Na₂SO₄,and filtered. Concentration of the filtrate under vacuum yielded amixture of p-methoxybenzylidene acetals. The mixture of acetals wasdissolved in toluene (0.4 ml) and the solution was cooled to 0° C. thena solution of diisobutylaluminum hydride (0.02 ml, 20M in toluene, 0.08mmol) was added. The resulting solution was stirred for 3.5 hours thenmethanol (0.1 ml) was added. The mixture was diluted with ethyl acetate(5 ml) and stirred with saturated aqueous sodium potassium tartrate for1.5 hours. The aqueous phase was separated and extracted with ethylacetate (2×10 ml) and the combined extracts were washed with brine anddried over Na₂SO₄. Filtration followed by concentration of the filtrateunder vacuum yielded 4.5 mg of crude material that was purified bysilica gel chromatography (30% ethyl acetate in hexanes eluent) to yield2.8 mg of 4-MPM-1,2,5,20-tetraol.

[0347] The mixture of formate p-methoxybenzyl ethers was dissolved inmethanol (0.1 ml) and 3% aqueous NH₄OH (0.1 ml) was added. The cloudymixture was stirred at room temperature for 30 minutes then rinsed intoethyl acetate over saturated aqueous NaHCO₃. The aqueous phase wasextracted with ethyl acetate (2×10 ml) and the combined extracts werewashed with brine, dried over Na₂SO₄, and filtered. Concentration of thefiltrate under vacuum yielded 4.8 mg of crude material which waspurified by silica gel chromatography to yield 3.2 mg of4-MPM-1,2,5,20-tetraol. Total combined yield of 4MPM-1,2,5,20-tetraol:68% from 25b.

[0348] 4-MPM-1,2,5,20-tetraol: ¹H NMR (500 MHz, CDCl₃) δ 0.13(s, 3H, TBSCH₃), 0.06 (s, 3H, TBS CH₃), 0.60 (q, J=8.0 Hz, 2H, TES CH₂), 0.89 (s,9H, TBS T-Bu), 0.95(t, J=8.0 Hz, TES CH₃), 0.97 (s, 3H, CH₃ 19), 1.22(s, 3H, CH₃ 17), 1.30 (s, 3H, CH₃ 16), 1.83 (dd, J=16.8,5.8 Hz, H9α),1.91 (q, J=12.4 Hz, 1H, H6β), 2.12 (m, 2H, H9α and 14β), 2.18 (s, 3H,CH₃ 18 ), 2.55 (m, 2H, H14β and 6α), 2.79 (d, J=5.3 Hz, 1H, H3α), 2.95(d, J=3.0 Hz, 1H, OH5), 3.54 (m, 1H, OH20), 3.66(dd, J=10.3, 5.3Hz, 1H,H2β), 3.81 (s, 3H, OCH₃), 3.85 (dd, J=5.2, 11.6 Hz, 1H, H7α), 3.91 (dt,J=5.9, 12.4, 1H, H5α), 4.18 (s, 1H, OH1), 4.13 (d, J=13 Hz, 1H, H20),4.20 (dd, J=7.22, 12.9 Hz, 1H, H20), 4.47 (d, J=11.8 Hz, 1H, OCH₂Ph),4.58 (m, 1H, H10β), 4.79 (d, J=11.8 Hz, 1H, OCH₂Ph), 4.85 (m, 1H, H13β),4.87 (d, J=6.8 Hz, 1H, OCH₂O), 5.01 (d, J=10.6 Hz, 1H, MPM CH₂), 5.10(d, J=6.8 Hz, 1H, OCH₂O), 5.11(d, J=10.6 Hz, 1H, MPM CH₂), 5.49(d,J=10.5 Hz, 1H, OH₂), 6.87 (d, J=8.7 Hz, 2H), 7.30 (d, J=8.7 Hz, 2H,p-MeOPh -o), 7.27-7.36 (m, 5H, p-MeOPh -m and Ph 7.36(m, 5H, p-MeOPh -mand P CH₂).

[0349] To a solution of the 4-MPM-1,2,5,20-tetraol (2.0 mg, 0.0023 mmol)stirred in 0.2 ml of CH₂Cl₂ and 0.02 ml of 2,2-dimethoxypropane at 0° C.was added a solution of p-toluenesulfonic acid (0.002 ml, 0.1 M in THF,0.0002 mmol). The resulting solution was stirred for 20 min thentriethylamine (0.1 ml) was added and stirring was continued for 10 min.The mixture was rinsed into ethyl acetate (10 ml) over saturated aqueousNaHCO₃ then the aqueous phase was extracted with ethyl acetate (2×5 ml).The combined extracts were washed with brine, dried with Na₂SO₄, andfiltered. Concentration of the filtrate under vacuum yielded 2.1 mg ofcrude material which was purified by silica gel chromatography to yield1.1 mg of acetonide 26b.

[0350] 26b (P₅₂₀=C(CH₃)₂, P₇=BOM): ¹H NMR (500 MHz, CDCl₃) δ-0.073 (s,3H, TBS CH₃), 0.008 (s, 3H, TBS CH₃), 0.60 (q, J=7.9 Hz, 6H, TES CH₂),0.79 (s, 9H, TBS t-Bu), 0.95(t, J=7.9 Hz, 9H, TES CH₃), 1.10 (s, 3H, CH₃19), 1.25 (s, 3H, CH₃ 17), 1.34 (s, 3H, CH₃ 16), 1.41 (s, 3H, CH₃acetonide), 1.46 (s, 3H, CH₃ acetonide), 1.88 (dd, J=16.7,5.5 Hz, H9β),2.08 (dd, J=14.3, 9.2 Hz, 1H, H14β), 2.17 (s, 3H, CH₃ 18), 2.21(dd,J=17.1, 1.7 Hz, 1H, H9α), 2.42 (dd, J=14.3,7.2 Hz, 1H, H14α), 2.61 (d,J=5.1 Hz, H3α), 2.62 (m, 1H, H6β), 3.71 (dd, J=11.3, 5.1 Hz, 1H, H2β),3.75 (dd, J=5.0, 11.3 Hz, 1H, H7α), 3.80 (s, 3H, OCH₃), 3.99 (dd,J=12.0, 6.2 Hz, 1H, H5α), 4.01 (d, J=14.2 Hz, 1H, H20), 4.17 (s, 1H,OH1), 4.44 (d, J=14.2 Hz, 1H, H20), 4.47 (d, J=11.6 Hz, 1H, OCH₂Ph),4.58 (m, 1H, H10β), 4.80 (d, J=11.6 Hz, 1H, OCH₂Ph), 4.84(d, J=11.3 Hz,1H, OH2), 4.85 (m, 1H, H13β), 4.88 (d, J=10.3 Hz, 1H, OCH₂O), 4.89 (d,J=6.8 Hz, 1H, MPM CH₂), 5.00 (d, J=10.3 Hz, 1H, OCH₂Ph), 5.10 (d, J=6.8Hz, 1H, MPM CH₂), 6.85 (d, J=8.9 Hz, 2H, p-MeOPh -o), 7.27 (d, J=8.9 Hz,2H, p-MeOPh -m), 7.27-7.36 (m, 5H, Ph CH₂).

[0351] Diolcarbonate 27b: To a solution of the diol 26b (P₅₂₀=C(CH₃)₂,P₇=BOM) (1.1 mg) in 0.2 mL of CH₂Cl₂ and 0.02 mL of pyridine stirred at−78° C. was added a solution of phosgene (0.010 mL, 2M in toluene, 0.02mmol). The resulting solution was stirred at −78° C. for 10 min thenwarmed to 0° C. for 3 h. The mixture was diluted with 30% ethyl acetatein hexanes (5 mL) then poured into 30% ethyl acetate in hexanes (10 mL)over saturated aqueous NaHCO₃. The aqueous phase was extracted with 30%ethyl acetate in hexanes (2×5 mL) then the combined extracts were washedwith brine, dried with Na₂SO₄, and filtered. Concentration of thefiltrate under vacuum yielded 1.3 mg of crude material. Purification bysilica gel chromatography yielded 0.9 mg of pure 1,2-cyclic carbonate.

[0352] To a solution of the carbonate stirred in 0.1 ml of THF and 0.05mL of methanol was added a solution of pyridinium tosylate (0.005 ml,0.1M in CH₂Cl₂). The mixture was stirred at room temperature for 24 hand partitioned between saturated sodium bicarbonate and ethyl acetate.The ethyl acetate layer was dried over sodium sulfate and evaporated togive 0.9 mg of diol 27b.

[0353] 27b (P₇=BOM): ¹H NMR (500 MHz, CDCl₃) δ-0.24 (s, 3H, TBS CH₃),−0.038 (s, 3H, TBS CH₃), 0.58 (q, J=8.1 Hz, 6H, TES CH₂), 0.84 (s, 9H,TBS t-Bu), 0.93(t, J=8.1 Hz, 9H, TES CH₃),1.14 (s, 3H, CH₃ 19), 1.19 (s,3H, CH₃ 17), 1.34 (s, 3H, CH₃ 16), 1.88 (br d, J=17 Hz, H9β), 2.00 (brq, J=12 Hz, 1H, H6β), 2.08 (d, J=1.4 Hz, 3H, CH₃ 18), 2.2 (m, 2H, H9αand 14β), 2.35 (br s, 1H, H3α), 2.39 (dt, J=4.8, 13 Hz, H6α), 2.74 (brs, 1h, 20 OH), 2.87 (dd, J=15.1 ,5.1 Hz, 1H, H14α), 3.71 (dd, J=11.3,5.1 Hz, 1h, H2β), 3.58 (br s, 2H, H7α and 20 OH), 3.78 (s, 3H, OCH₃),3.78 (br m, 1H, H5α), 4.37 (dd, J=13.0, 5.8 Hz, 1H, H20), 4.39 (dd,J=4.8, 5.8 Hz, 1H, H10β), 4.47 (m, 2H, H20and 2β), 4.59 (d, J=11.6 Hz,1H, OCH₂Ph), 4.63 (br m, 1H, H13β), 4.71 (d, J=11.6 Hz, 1H, OCH₂Ph),4.88 (d, J=7.2 Hz, 1H, OCH₂O),4.91 (d, J=7.2 Hz, 1H, OCH₂O), 4.93 (m,2H, MPM CH₂), 6.84 (d, J=8.6 Hz, 2H, p-MeOPh -o), 7.23 (d, J=8.6 Hz, 2H,p-MeOPh -m), 7.27-7.36 (m, 5H, Ph CH₂ ).

[0354] Mesylate 28b. To a stirred solution of diol 27b (0.9 mg) inpyridine (0.6 mL) under nitrogen at 0° C. was added dropwisemethanesulfonyl chloride (0.02 mL). After 12 h, a saturated aqueousNaHCO₃ solution (0.05 mL) was added. The mixture was stirred for 10 min,poured into 20 mL of a saturated aqueous NaHCO₃ solution and extractedwith 40% ethyl acetate/hexane (20 mL ×3). The combined organic phase wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive 1 mg of 28b as a colorless oil.

[0355] Oxetane 29. To a stirred solution of mesylate 28b (1 mg) intoluene (0.4 mL) under nitrogen at room temperature was addeddiisopropyl ethylamine (0.008 mL). The solution was refluxed for 3.5 h,cooled to room temperature, poured into 20 mL of a saturated aqueousNaHCO₃ solution and extracted with ethyl acetate (20 mL ×3 ). Thecombined organic phase was dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure to give 1.5 mg of a pale yellow oil. The oil wascolumn chromatographed (30% ethyl acetate/hexane) to yield 1 mg of MPMoxetane. This material was dissolved in 1 mL of methylene chloride, 0.1mL of 0.1 M phosphate buffer and 1 mg of DDQ were added, and the mixturewas stirred at ambient temperature for 2 h. The mixture was poured into20 mL of a saturated aqueous NaHCO₃ solution and extracted with ethylacetate (20 mL ×3 ). The combined organic phase was dried over anhydrousNa₂SO₄, and concentrated under reduced pressure to give 1.0 mg of anoil. To a stirred solution of this material (1 mg) and dimethylaminopyridine (1.5 mg) in pyridine (10 μL) under nitrogen at roomtemperature was added acetic anhydride (5 μL). The solution was stirredfor 15 h, diluted with ethyl acetate, poured into 20 mL of a 10% aqueousCuSO₄ solution and extracted with ethyl acetate (20 mL ×3). The combinedorganic phase was washed with a saturated aqueous NaHCO₃ solution, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to give 2mg of a pale yellow oil. The oil was column chromatographed (25% ethylacetate/hexane) to yield 0.6 mg of oxetane 29.

[0356] In view of the above, it will be seen that the several objects ofthe invention are achieved.

[0357] As various changes could be made in the above compositionswithout departing from the scope of the invention, it is intended thatall matter contained in the above description be interpreted asillustrative and not in a limiting sense.

What we claim is:
 1. An intermediate for use in the preparation of atricyclic or tetracyclic taxane having the formula:

wherein R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, ortogether with R₂ is a carbonate; R₂ is hydrogen, hydroxy, protectedhydroxy, oxo, or —OCOR₃₁, or together with R₁ is a carbonate; R₃ ishydrogen, hydroxy, protected hydroxy, —OCOR₃₂, or oxo; R₈ is hydrogen,alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₉ is hydrogen, hydroxy,protected hydroxy, oxo, or —OCOR₃₃, or together with R₁₀ is a carbonate;R₁₀ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₂₉, ortogether with R₉ is a carbonate; R₁₃ is hydrogen, hydroxy, protectedhydroxy, —OCOR₃₅ or MO—; R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₅ areindependently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy,—NX₈X₁₀, —SX₁₀, monocyclic aryl or monocyclic heteroaryl; X₈ ishydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X₁₀is alkyl,alkenyl, alkynyl, aryl, or heteroaryl; and M comprises ammonium or is ametal.
 2. An intermediate for use in the preparation of a tricyclic ortetracyclic taxane having the formula:

wherein R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, ortogether with R₂ is a carbonate; R₂ is hydrogen, hydroxy, protectedhydroxy, oxo, or —OCOR₃₁, or together with R₁ is a carbonate; R₃ ishydrogen, hydroxy, protected hydroxy, —OCOR₃₂, or oxo, or together withR_(7b) is a carbonate; R_(7b) is hydrogen, alkyl, cyano, hydroxy,protected hydroxy, or —OCOR₃₆, or together with R₃ or R₉ is a carbonate;R_(7c) and R_(7d) are independently hydrogen, alkyl, alkenyl, alkynyl,aryl or heteroaryl; R₉ is hydrogen, hydroxy, protected hydroxy, oxo, or—OCOR₃₃, or together with R_(7b) or R₁₀ is a carbonate; R₁₀ is hydrogen,hydroxy, protected hydroxy, oxo, or —OCOR₂₉, or together with R₉ is acarbonate; R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅ or MO—;R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₅ and R₃₆ are independently hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryloxy, —NX₈ X₁₀, —SX₁₀, monocyclic aryl ormonocyclic heteroaryl; X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl; X₁₀is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and Mcomprises ammonium or is a metal.
 3. An intermediate for use in thepreparation of a tricyclic or tetracyclic taxane having the formula:

wherein R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, ortogether with R₂ is a carbonate; R₂ is hydrogen, hydroxy, protectedhydroxy, oxo, or —OCOR₃₁, or together with R₁ is a carbonate; R₃ ishydrogen, hydroxy, protected hydroxy, or —OCOR₃₂; R_(7b) is hydrogen,alkyl, cyano, hydroxy, protected hydroxy, or —OCOR₃₆; R_(7c) ishydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₉ is hydrogen,hydroxy, protected hydroxy, oxo, or —OCOR₃₃, or together with R₁₀ is acarbonate; R₁₀ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₂₉,or together with R₉ is a carbonate; R₁₃ is hydrogen, hydroxy, protectedhydroxy, —OCOR₃₅ or MO—; R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₅ and R₃₆ areindependently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy,—NX₈X₁₀, —SX₁₀, monocyclic aryl or monocyclic heteroaryl; X₈ ishydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X₁₀, is alkyl,alkenyl, alkynyl, aryl, or heteroaryl; and M comprises ammonium or is ametal.
 4. An intermediate for use in the preparation of a tricyclic ortetracyclic taxane having the formula:

wherein R is C₁-C₈ alkyl, R₁ is hydrogen, hydroxy, protected hydroxy or—OCOR₃₀, or together with R₂ is a carbonate; R₂ is hydrogen, hydroxy,protected hydroxy, oxo, or —OCOR₃₁, together with R₁ is a carbonate, ortogether with R_(4a) is a carbonate; R_(4a) is hydrogen, alkyl, hydroxy,protected hydroxy, or —OCOR₂₇, or together with R₂ is a carbonate;R_(7a) is hydrogen, halogen, hydroxy, protected hydroxy, —OR₂₈, or—OCOR₃₄, or together with R₉ is a carbonate; R₉ is hydrogen, oxo,hydroxy, protected hydroxy, —OR₂₈, or —OCOR₃₃, or together with R_(7a)or R₁₀ is a carbonate; R₁₀ is hydrogen, oxo, hydroxy, protected hydroxy,—OR₂₈, or -OCOR₂₉, or together with R₉ is a carbonate; R₁₃ is hydrogen,hydroxy, protected hydroxy, —OCOR₃₅ or MO—; R₂₈ is a functional groupwhich increases the solubility of the taxane derivative; R₂₉, R₃₀, R₃₁,R₃₃, R₃₄ and R₃₅ are independently hydrogen, alkyl, alkenyl, alkynyl,alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclic aryl or monocyclicheteroaryl; X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl; X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and Mcomprises ammonium or is a metal.
 5. An intermediate for use in thepreparation of a tricyclic or tetracyclic taxane having the formula:

wherein R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, ortogether with R₂ is a carbonate; R₂ is hydrogen, hydroxy, protectedhydroxy, oxo, or —OCOR₃₁, or together with R₁ or R_(4a) is a carbonate;R_(4a) is hydrogen, alkyl, hydroxy, protected hydroxy, or —OCOR₂₇,together with R_(4b) is an oxo, or together with R₂, R_(4b), or R₅ is acarbonate; R_(4b) is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, or cyano, together with R_(4a) is an oxo, together withR_(4a) or R₅ is a carbonate, or together with R₅ and the carbons towhich they are attached form an oxetane ring; R₅ is hydrogen, hydroxy,protected hydroxy, —OCOR₃₇, oxo, together with R_(4a) or R_(4b) is acarbonate, or together with R_(4b) and the carbons to which they areattached form an oxetane ring; R_(7a) is hydrogen, halogen, hydroxy,protected hydroxy, —OR₂₈, or —OCOR₃₄, or together with R₉ is acarbonate; R₉ is hydrogen, oxo, hydroxy, protected hydroxy, —OR₂₈, or—OCOR₃₃, or together with R_(7a) or R₁₀ is a carbonate; R₁₀ is hydrogen,oxo, hydroxy, protected hydroxy, —OR₂₈, or —OCOR₂₉, or together with R₉is a carbonate; R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅,MO— or

R₂₈ is a functional group which increases the solubility of the taxanederivative; R₂₇, R₂₉, R₃₀, R₃₁, R₃₃, R₃₄, R₃₅ and R₃₇ are independentlyhydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀,monocyclic aryl or monocyclic heteroaryl; X₁ is —OX₆, —SX₇, or —NX₈X₉;X₂ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X₃ and X₄are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl; X₅ is —COX₁₀, —COOX₁₀, —COSX₁₀, —CONX₈X₁₀, or —SO₂X₁₁; X₆ ishydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protectinggroup, or a functional group which increases the water solubility of thetaxane derivative; X₇ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, orsulfhydryl protecting group; X₈ is hydrogen, alkyl, alkenyl, alkynyl,aryl, or heteroaryl; X₉ is an amino protecting group; X₁₀ is alkyl,alkenyl, alkynyl, aryl, or heteroaryl; X₁₁ is alkyl, alkenyl, alkynyl,aryl, heteroaryl, —OX₁₀, or —NX₈X₁₄; X₁₄ is hydrogen, alkyl, alkenyl,alkynyl, aryl, or heteroaryl; and M comprises ammonium or is a metal. 6.An intermediate for use in the preparation of taxol or other tricyclicor tetracyclic taxanes selected from the group consisting of

wherein R is lower alkyl; T₄ is hydroxy or protected hydroxy; T_(4a) andT_(4b) are independently alkoxy, alkoxycarbonyloxy, acyloxy,sulfonyloxy, hydroxy, or protected hydroxy, or together form acarbonate; T₅ is alkoxy, alkoxycarbonyloxy, acyloxy, sulfonyloxy,hydroxy, or protected hydroxy; P₅, P₇, P₁₀ and P₁₃ are each a hydroxyprotecting group; R₂ is hydrogen, hydroxy, or —OCOR₃₁; R_(4a) ishydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, or—OCOR₃₀; R_(7a) is hydrogen, halogen, protected hydroxy, or —OR₂₈;R_(10a) is hydrogen, —OCOR₂₉, hydroxy, or protected hydroxy; R₁₃ ishydroxy, protected hydroxy, MO— or

R₂₈ is hydrogen, acyl, hydroxy protecting group or a functional groupwhich increases the solubility of the taxane derivative; R₂₉, R₃₀, andR₃₁ are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic arylor monocyclic heteroaryl; X₁ is —OX₆, —SX₇, or —NX₈X₉; X₂ is hydrogen,alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X₃ and X₄ areindependently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X₅is —COX₁₀, —COOX₁₀, —COSX₁₀, —CONX₈X₁₀, or —SO₂X₁₁; X₆ is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, ora functional group which increases the water solubility of the taxanederivative; X₇ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, orsulfhydryl protecting group; X₈ is hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl orheteroaryl; X₉ is an amino protecting group; X₁₀ is alkyl, alkenyl,alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl alkynyl,aryl or heteroaryl; X₁₁ is alkyl, alkenyl, alkynyl, aryl, heteroaryl,—OX₁₀, or —NX₈X₁₄; X₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl; and M comprises ammonium or is a metal.